piperidines and Cognition-Disorders

Alzheimer's disease is the most common cause of dementia in older people. One approach to symptomatic treatment of Alzheimer's disease is to enhance cholinergic neurotransmission in the brain by blocking the action of the enzyme responsible for the breakdown of the neurotransmitter acetylcholine. This can be done by a group of drugs known as cholinesterase inhibitors. Donepezil is a cholinesterase inhibitor.This review is an updated version of a review first published in 1998.. To assess the clinical efficacy and safety of donepezil in people with mild, moderate or severe dementia due to Alzheimer's disease; to compare the efficacy and safety of different doses of donepezil; and to assess the effect of donepezil on healthcare resource use and costs.. We searched Cochrane Dementia and Cognitive Improvement's Specialized Register, MEDLINE, Embase, PsycINFO and a number of other sources on 20 May 2017 to ensure that the search was as comprehensive and up-to-date as possible. In addition, we contacted members of the Donepezil Study Group and Eisai Inc.. We included all double-blind, randomised controlled trials in which treatment with donepezil was administered to people with mild, moderate or severe dementia due to Alzheimer's disease for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two different doses of donepezil were compared.. One reviewer (JSB) extracted data on cognitive function, activities of daily living, behavioural symptoms, global clinical state, quality of life, adverse events, deaths and healthcare resource costs. Where appropriate and possible, we estimated pooled treatment effects. We used GRADE methods to assess the quality of the evidence for each outcome.. Thirty studies involving 8257 participants met the inclusion criteria of the review, of which 28 studies reported results in sufficient detail for the meta-analyses. Most studies were of six months' duration or less. Only one small trial lasted 52 weeks. The studies tested mainly donepezil capsules at a dose of 5 mg/day or 10 mg/day. Two studies tested a slow-release oral formulation that delivered 23 mg/day. Participants in 21 studies had mild to moderate disease, in five studies moderate to severe, and in four severe disease. Seventeen studies were industry funded or sponsored, four studies were funded independently of industry and for nine studies there was no information on source of funding.Our main analysis compared the safety and efficacy of donepezil 10 mg/day with placebo at 24 to 26 weeks of treatment. Thirteen studies contributed data from 3396 participants to this analysis. Eleven of these studies were multicentre studies. Seven studies recruited patients with mild to moderate Alzheimer's disease, two with moderate to severe, and four with severe Alzheimer's disease, with a mean age of about 75 years. Almost all evidence was of moderate quality, downgraded due to study limitations.After 26 weeks of treatment, donepezil compared with placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog, range 0 to 70) (mean difference (MD) -2.67, 95% confidence interval (CI) -3.31 to -2.02, 1130 participants, 5 studies), the Mini-Mental State Examination (MMSE) score (MD 1.05, 95% CI 0.73 to 1.37, 1757 participants, 7 studies) and the Severe Impairment Battery (SIB, range 0 to 100) (MD 5.92, 95% CI 4.53 to 7.31, 1348 participants, 5 studies). Donepezil was also associated with better function measured with the Alzheimer's Disease Cooperative Study activities of daily living score for severe Alzheimer's disease (ADCS-ADL-sev) (MD 1.03, 95% CI 0.21 to 1.85, 733 participants, 3 studies). A higher proportion of participants treated with donepezil experienced improvement on the clinician-rated global impression of change scale (odds ratio (OR) 1.92, 95% CI 1.54 to 2.39, 1674 participants, 6 studies). There was no difference between donepezil and placebo for behavioural symptoms measured by the Neuropsychiatric Inventory (NPI) (MD -1.62, 95% CI -3.43 to 0.19, 1035 participants, 4 studies) or by the Behavioural Pathology in Alzheimer's Disease (BEHAVE-AD) scale (MD 0.4, 95% CI -1.. There is moderate-quality evidence that people with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12 or 24 weeks with donepezil experience small benefits in cognitive function, activities of daily living and clinician-rated global clinical state. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total healthcare resource costs. Benefits on 23 mg/day were no greater than on 10 mg/day, and benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose, but the rates of withdrawal and of adverse events before end of treatment were higher the higher the dose.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

Cognition deficit is one of the most common symptoms of schizophrenia, including abstract thinking and memory, and attention deficits. Previous studies have suggested that the improvement of cognition is very important for the recovery of disease and social function for the patients. Recent studies indicated that two new atypical antipsychotics, blonanserin and lurasidone, are expected to improve the cognitive impairment in patients with schizophrenia. This review introduces pathogenesis of cognitive impairment in schizophrenia, mechanisms of blonanserin and lurasidone in the improvement of cognitive impairment and progress in their clinical application for schizophrenia. We hope that this review could guide clinical use of antipsychotics and provide new directions for future studies.. 认知功能障碍是精神分裂症常见症状之一，主要表现为抽象思维、记忆、注意等方面的障碍。认知功能的改善对患者疾病康复、社会功能恢复具有至关重要的意义。近来研究表明新型非典型抗精神病药物布南色林和鲁拉西酮具有独特的受体作用机制，有望使患者认知功能障碍得到更好的改善。笔者从精神分裂症患者认知功能障碍的病因机制入手，综述布南色林和鲁拉西酮改善精神分裂症患者认知功能的作用机制；介绍两种药物的临床应用进展，以便更好地指导临床用药，为进一步研究提供新方向。.

Topics: Antipsychotic Agents; Cognition Disorders; Humans; Lurasidone Hydrochloride; Piperazines; Piperidines; Schizophrenia; Schizophrenic Psychology

Prevention of cognitive impairment and dementia is an important public health goal. Epidemiological evidence shows a relationship between cognitive impairment and Type 2 diabetes mellitus. The risk of dementia increases with duration of disease. This updated systematic review investigated the effect on cognitive function of the type of treatment and level of metabolic control in people with Type 2 diabetes.. To assess the effects of different strategies for managing Type 2 diabetes mellitus on cognitive function and the incidence of dementia.. We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG)), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL and LILACS on 15 October 2016. ALOIS contains records from all major health care databases, (CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS), as well as from many trials' registers and grey literature sources.. We included randomised controlled trials (RCTs) which compared two or more different treatments for Type 2 diabetes mellitus and in which cognitive function was measured at baseline and after treatment.. Two review authors independently extracted data and assessed the quality of the included RCTs. We pooled data for comparable trials and estimated the effects of treatment by using risk ratios (RRs) and mean differences (MDs), according to the nature of the outcome. We assessed the quality of the evidence using GRADE methods.. We identified seven eligible studies but only four provided data we could include in efficacy analyses. Two of these studies compared intensive versus standard glycaemic control and two compared different pharmacological treatments. All studies were at unclear risk of bias in at least two domains and one large study was at high risk of performance and detection bias.(a) Two studies with 13,934 participants at high cardiovascular risk provided efficacy data on intensive versus standard glycaemic control. A third study with 1791 participants provided additional data on hypoglycaemic episodes and mortality. There is probably no difference between treatment groups in the number of participants who decline by at least 3 points on the Mini-Mental State Examination (MMSE) over five years (RR 0.98, 95% CI 0.88 to 1.08; 1 study; n = 11,140; moderate-quality evidence); and there may also be little or no difference in the incidence of dementia (RR 1.27, 95% CI 0.87 to 1.85; 1 study; n = 11,140; low-quality evidence). From another study, there was probably little or no difference in MMSE score after 40 months (MD -0.01, 95% CI -0.18 to 0.16; 1 study; n = 2794; moderate quality evidence). Participants exposed to the intensive glycaemic control strategy probably experience more episodes of severe hypoglycaemia than those who have standard treatment (RR 2.18, 95% CI 1.52 to 3.14; 2 studies; n = 12,827; moderate-quality evidence). The evidence from these trials suggests that the intensity of glycaemic control may have little or no effect on all-cause mortality (RR 0.99, 95% CI 0.87 to 1.13; 3 studies; n = 15,888; low-quality evidence).(b) One study with 156 participants compared glibenclamide (glyburide) with repaglinide. There may be a small advantage of glibenclamide on global cognitive function measured with the MMSE after 12 months (MD -0.90, 95% CI -1.68 to -0.12; low-quality evidence). No data were reported on the incidence of dementia, hypoglycaemic events or all-cause mortality.(c) One study with 145 participants compared rosiglitazone plus metformin to glibenclamide (glyburide) plus metformin over 24 weeks. It reported only on cognitive subdomains and not on global cognitive function, incidence of MCI or dementia, hypoglycaemic events or all causes of mortality.. We found no good evidence that any specific treatment or treatment strategy for Type 2 diabetes can prevent or delay cognitive impairment. The best available evidence related to the comparison of intensive with standard glycaemic control strategies. Here there was moderate-quality evidence that the strategies do not differ in their effect on global cognitive functioning over 40 to 60 months.

Topics: Carbamates; Cause of Death; Cognition Disorders; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Memory Disorders; Metformin; Piperidines; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazolidinediones

The prevalence of Alzheimer's disease (AD) continues to rise, while treatment options for cognitive impairment are limited. Acetylcholinesterase inhibitors (AChEIs) aim to provide symptomatic benefit for cognitive decline, however these drugs are not without adverse events (AEs). The safety profile of each drug must be taken carefully into consideration before being prescribed, as new dosages and formulations have recently been approved. Areas covered: Donepezil, galantamine and rivastigmine are the three AChEIs approved for the treatment of varying stages of AD. Numerous clinical trials and post-marketing studies have evaluated the safety of these medications. This article will review the safety, efficacy and tolerability of these drugs in treating AD. Topics including pharmacovigilance databases, concomitant drug interactions, prescribing cascades, and treatment discontinuation are also covered. Expert opinion: AChEI use in those with mild, moderate or severe AD provide modest improvements in cognition, function and behavior. The pharmacological treatment of AD using AChEIs is associated with generally mild AEs. Differences in drug formulations should be taken into account when determining the most appropriate route of administration for each individual. Furthermore, discontinuation of AChEIs must be carefully monitored as it may be associated with worsening cognitive impairment.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Drug Interactions; Galantamine; Humans; Indans; Piperidines; Rivastigmine; Severity of Illness Index

Dopamine depletion is one of the most important features of Parkinson's Disease (PD). However, insufficient response to dopaminergic replacement therapy suggests the involvement of other neurotransmitter systems in the pathophysiology of PD. Cholinergic degeneration contributes to gait impairments, cognitive impairment, psychosis, and REM-sleep disturbances, among other symptoms. Areas covered: In this review, we explore the idea that enhancing cholinergic tone by pharmacological or neurosurgical procedures could be a first-line therapeutic strategy for the treatment of symptoms derived from cholinergic degeneration in PD. Expert opinion: Rivastigmine, a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase, is effective for dementia, whereas the use of Donepezil is still in the realm of investigation. Interesting results suggest the efficacy of these drugs in the treatment of gait dysfunction. Evidence on the clinical effects of these drugs for psychosis and REM-sleep disturbances is still weak. Stimulation of the pedunculo-pontine tegmental nuclei (which provide cholinergic innervation to the brain stem and subcortical nuclei) has also been used with some success for the treatment of gait dysfunction. Anticholinergic drugs should be used with caution in PD, as they may aggravate cholinergic symptoms. Notwithstanding, in some patients they might help control parkinsonian motor symptoms.

Topics: Animals; Cholinergic Agents; Cholinergic Neurons; Clinical Trials as Topic; Cognition Disorders; Dementia; Donepezil; Gait; Humans; Indans; Nerve Degeneration; Parkinson Disease; Piperidines; Psychotic Disorders

Neuropsychiatric symptoms are common in Alzheimer's disease (AD) and other neurodegenerative disorders. Recent progress has been made with clinical trials, advancing new therapies for psychosis in Parkinson's disease (PD), agitation in AD, and apathy in AD. Definitions have emerged for agitation and apathy in patients with cognitive impairment, facilitating recruitment of clinical trial populations. Progress in clinical trial design and the agents being assessed promise to advance therapies for disabling symptoms and improve quality of life for patients and caregivers.

Topics: Alzheimer Disease; Apathy; Citalopram; Clinical Trials as Topic; Cognition Disorders; Humans; Mental Disorders; Piperidines; Research Design; Therapies, Investigational; Treatment Outcome; Urea

People with Down syndrome are vulnerable to developing dementia at an earlier age than the general population. Alzheimer's disease and cognitive decline in people with Down syndrome can place a significant burden on both the person with Down syndrome and their family and carers. Various pharmacological interventions, including donepezil, galantamine, memantine and rivastigmine, appear to have some effect in treating cognitive decline in people without Down syndrome, but their effectiveness for those with Down syndrome remains unclear.. To assess the effectiveness of anti-dementia pharmacological interventions and nutritional supplements for treating cognitive decline in people with Down syndrome.. In January 2015, we searched CENTRAL, ALOIS (the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group), Ovid MEDLINE, Embase, PsycINFO, seven other databases, and two trials registers. In addition, we checked the references of relevant reviews and studies and contacted study authors, other researchers and relevant drug manufacturers to identify additional studies.. Randomised controlled trials (RCTs) of anti-dementia pharmacological interventions or nutritional supplements for adults (aged 18 years and older) with Down syndrome, in which treatment was administered and compared with either placebo or no treatment.. Two review authors independently assessed the risk of bias of included trials and extracted the relevant data. Review authors contacted study authors to obtain missing information where necessary.. Only nine studies (427 participants) met the inclusion criteria for this review. Four of these (192 participants) assessed the effectiveness of donepezil, two (139 participants) assessed memantine, one (21 participants) assessed simvastatin, one study (35 participants) assessed antioxidants, and one study (40 participants) assessed acetyl-L-carnitine.Five studies focused on adults aged 45 to 55 years, while the remaining four studies focused on adults aged 20 to 29 years. Seven studies were conducted in either the USA or UK, one between Norway and the UK, and one in Japan. Follow-up periods in studies ranged from four weeks to two years. The reviewers judged all included studies to be at low or unclear risk of bias.Analyses indicate that for participants who received donepezil, scores in measures of cognitive functioning (standardised mean difference (SMD) 0.52, 95% confidence interval (CI) -0.27 to 1.13) and measures of behaviour (SMD 0.42, 95% CI -0.06 to 0.89) were similar to those who received placebo. However, participants who received donepezil were significantly more likely to experience an adverse event (odds ratio (OR) 0.32, 95% CI 0.16 to 0.62). The quality of this body of evidence was low. None of the included donepezil studies reported data for carer stress, institutional/home care, or death.For participants who received memantine, scores in measures of cognitive functioning (SMD 0.05, 95% CI -0.43 to 0.52), behaviour (SMD -0.17, 95% CI -0.46 to 0.11), and occurrence of adverse events (OR 0.45, 95% CI 0.18 to 1.17) were similar to those who received placebo. The quality of this body of evidence was low. None of the included memantine studies reported data for carer stress, institutional/home care, or death.Due to insufficient data, it was possible to provide a narrative account only of the outcomes for simvastatin, antioxidants, and acetyl-L-carnitine. Results from one pilot study suggest that participants who received simvastatin may have shown a slight improvement in cognitive measures.. Due to the low quality of the body of evidence in this review, it is difficult to draw conclusions about the effectiveness of any pharmacological intervention for cognitive decline in people with Down syndrome.

Topics: Acetylcarnitine; Adult; Antioxidants; Cognition; Cognition Disorders; Donepezil; Down Syndrome; Humans; Indans; Memantine; Middle Aged; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Simvastatin

Traumatic brain injury (TBI) is a major cause of chronic disability. Worldwide, it is the leading cause of disability in the under 40s, resulting in severe disability in some 150 to 200 million people per annum. In addition to mood and behavioural problems, cognition-particularly memory, attention and executive function-are commonly impaired by TBI. Cognitive problems following TBI are one of the most important factors in determining people's subjective well-being and their quality of life. Drugs are widely used in an attempt to improve cognitive functions. Whilst cholinergic agents in TBI have been reviewed, there has not yet been a systematic review or meta-analysis of the effect on chronic cognitive problems of all centrally acting pharmacological agents.. To assess the effects of centrally acting pharmacological agents for treatment of chronic cognitive impairment subsequent to traumatic brain injury in adults.. We searched ALOIS-the Cochrane Dementia and Cognitive Improvement Group's Specialised Register-on 16 November 2013, 23 February 2013, 20 January 2014, and 30 December 2014 using the terms: traumatic OR TBI OR "brain injury" OR "brain injuries" OR TBIs OR "axonal injury" OR "axonal injuries". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Supplementary searches were also performed in MEDLINE, EMBASE, PsycINFO, The Cochrane Library, CINAHL, LILACs, ClinicalTrials.gov, the World Health Organization (WHO) Portal (ICTRP) and Web of Science with conference proceedings.. We included randomised controlled trials (RCTs) assessing the effectiveness of any one centrally acting pharmacological agent that affects one or more of the main neurotransmitter systems in people with chronic traumatic brain injury; and there had to be a minimum of 12 months between the injury and entry into the trial.. Two review authors examined titles and abstracts of citations obtained from the search. Relevant articles were retrieved for further assessment. A bibliographic search of relevant papers was conducted. We extracted data using a standardised tool, which included data on the incidence of adverse effects. Where necessary we requested additional unpublished data from study authors. Risk of bias was assessed by a single author.. Only four studies met the criteria for inclusion, with a total of 274 participants. Four pharmacological agents were investigated: modafinil (51 participants); (-)-OSU6162, a monoamine stabiliser (12 participants of which six had a TBI); atomoxetine (60 participants); and rivastigmine (157 participants). A meta-analysis could not be performed due to the small number and heterogeneity of the studies.All studies examined cognitive performance, with the majority of the psychometric sub-tests showing no difference between treatment and placebo (n = 274, very low quality evidence). For (-)-OSU6162 modest superiority over placebo was demonstrated on three measures, but markedly inferior performance on another. Rivastigmine was better than placebo on one primary measure, and a single cognitive outcome in a secondary analysis of a subgroup with more severe memory impairment at baseline. The study of modafinil assessed clinical global improvement (n = 51, low quality evidence), and did not find any difference between treatment and placebo. Safety, as measured by adverse events, was reported by all studies (n = 274, very low quality evidence), with significantly more nausea reported by participants who received rivastigmine compared to placebo. There were no other differences in safety between treatment and placebo. No studies reported any deaths.. There is insufficient evidence to determine whether pharmacological treatment is effective in chronic cognitive impairment in TBI. Whilst there is a positive finding for rivastigmine on one primary measure, all other primary measures were not better than placebo. The positive findings for (-)-OSU6162 are interpreted cautiously as the study was small (n = 6). For modafinil and atomoxetine no positive effects were found. All four drugs appear to be relatively well tolerated, although evidence is sparse.

Topics: Adolescent; Adult; Aged; Atomoxetine Hydrochloride; Benzhydryl Compounds; Brain Injuries; Chronic Disease; Cognition; Cognition Disorders; Humans; Middle Aged; Modafinil; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Various studies highlight cognitive impairments in cancer patients. This paper proposes a review of longitudinal controlled studies evaluating the efficacy of interventions aiming to reduce these cognitive impairments. Longitudinal controlled studies evaluating the efficacy of interventions aiming to reduce cognitive impairments in adult cancer patients and published between 1993 and 2013 were identified, with the exception of studies that implied patients suffering from CNS tumor or metastasis. Pharmacological interventions (n = 11) suggested the positive impact of modafinil on memory and executive functions. Non-pharmacological interventions (n = 10) suggested the positive impact of cognitive revalidation and stimulation programs, psycho-education and meditation on several memory, attentional and executive objective as well as subjective functions. Non-pharmacological interventions show more significant cognitive benefits than pharmacological interventions. Some longitudinal controlled studies support the usefulness of interventions aiming to reduce cognitive impairments in cancer patients. Further studies should evaluate the effectiveness of programs combining technics aiming to reduce cognitive impairments and psychotherapeutic technics aiming to support patients' coping with illness.

Topics: Adult; Benzhydryl Compounds; Case-Control Studies; Central Nervous System Stimulants; Cognition; Cognition Disorders; Darbepoetin alfa; Donepezil; Erythropoietin; Estradiol; Executive Function; Female; Humans; Indans; Longitudinal Studies; Male; Meditation; Methylphenidate; Modafinil; Neoplasms; Piperidines

Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear.. To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adult patients treated with cranial irradiation.. In August 2014. we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO and checked the reference lists of included studies. We also searched for ongoing trials via ClinicalTrials.gov, the Physicians Data Query and the Meta Register of Controlled Trials.. We included randomised controlled trials (RCTs) that evaluated pharmacological or non-pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure.. Two review authors (JD, KZ) independently extracted data from selected studies and carried out a 'Risk of bias' assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled.. Sixteen studies were identified for possible inclusion in the review, six of which were included. Three studies investigated prevention and three studies investigated amelioration. Due to differences between studies in the interventions being evaluated, a meta-analysis was not possible. Two studies investigated a pharmacological intervention for the prevention of cognitive deficits; memantine compared with placebo, and d-threo-methylphenidate HCL compared with placebo. In the first study the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The second study found no statistically significant difference between arms, with few adverse events. The third study investigated a rehabilitation program for the prevention of cognitive deficits but did not carry out a statistical comparison of cognitive performance between groups.Three studies investigated the use of a pharmacological intervention for the treatment of cognitive deficits; methylphenidate compared with modafinil, two different doses of modafinil, and donepezil compared with placebo. The first study found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. The second study combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The third study did not find an improvement in the primary cognitive outcome of overall performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. No non-pharmacological studies for the amelioration of cognitive deficits were eligible. There were a number of limitations across studies but few without high risks of bias.. There is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil may have a role in treating cognitive deficits in adults with primary or metastatic brain tumours who have been treated with cranial irradiation. Patient withdrawal affected the statistical power of both studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher quality of evidence.There is no strong evidence to support any non-pharmacological interventions (medical or cognitive/behavioural) in the prevention or amelioration of cognitive deficits. Non-randomised studies appear promising but are as yet to be conclusive via translation into high quality evidence. Further research is required.

Topics: Adult; Benzhydryl Compounds; Cognition Disorders; Cranial Irradiation; Donepezil; Humans; Indans; Memantine; Methylphenidate; Modafinil; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

The drugs currently available for the treatment of Alzheimer's disease and other dementias can provide limited symptomatic improvement. The acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine and the NMDA-receptor antagonist memantine have produced modest but apparently persistent improvements in cognition, activities of daily living, and behavior in patients with disease severity ranging from mild to severe. Among the acetylcholinesterase inhibitors, transdermal rivastigmine causes fewer gastrointestinal side effects than the oral formulation. Whether adding memantine to an acetylcholinesterase inhibitor is more effective than an acetylcholinesterase inhibitor alone remains to be established; clinical trial results have been mixed. None of these agents have been shown to stop or reverse the underlying neurodegenerative process.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate; Rivastigmine

Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction.

Topics: Antineoplastic Agents; Central Nervous System Stimulants; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Memantine; Neoplasms; Piperidines

Even though cognitive impairment is manifested in almost all patients with schizophrenia, the Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study showed no significant difference between first- and second-generation psychotropic drugs in improving cognitive abilities. Discovering new drugs that can improve impaired cognition, thus, is an attractive treatment target for patients with schizophrenia.. This article briefly reviews about donepezil, a highly selective (IC(50) = 6.7 nM) centrally acting reversible acetylcholinesterase inhibitor that has been approved by FDA for treating cognitive deficit states such as in Alzheimer's disease and its uses in clinical trials for the treatment of schizophrenia. The literature search included PubMed and Cochrane library with the following words: donepezil, schizophrenia and cognitive impairments.. The results of several clinical trials utilizing donepezil as an adjunct to second-generation antipsychotic drugs targeting cognitive deficits in schizophrenia subjects have been disappointing and would not lead clinicians to consider this as a potential treatment option. While longer randomized controlled trials, increase dosage and selected groups of patients at different stage of cognitive impairment may provide a better understanding of the potential for this drug in addressing cognitive deficits, results to date have not been encouraging.

Topics: Binding Sites; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Models, Molecular; Molecular Structure; Piperidines; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

To review the primary literature regarding the use of cholinesterase inhibitors (ChEIs) as adjunctive therapy for cognitive enhancement and improvement of depressive symptoms for older adults with depression.. A literature search of MEDLINE (1950-September 2011) was conducted, using the search term depression in combination with cholinesterase inhibitor, donepezil, galantamine, or rivastigmine. A search of reference citations was conducted to identify additional references.. English-language clinical trials were evaluated. Studies that included subjects with Alzheimer's disease, dementia, Parkinson disease, bipolar disorder, or schizophrenia were excluded. Four clinical studies met our criteria.. We identified 4 randomized, double-blind, placebo-controlled trials that ranged in sample size from 20 to 130. Galantamine 16 mg daily was evaluated in 2 trials lasting 8 and 24 weeks. Neither study found a statistically significant difference in measures of cognition or Hamilton Rating Scale for Depression scores. Donepezil augmentation was evaluated in a 1-year and a 2-year trial. Donepezil was found to improve global cognition at 1 year, but the benefit did not persist at year 2. Subjects with mild cognitive impairment at baseline who received donepezil experienced higher depression recurrence than did those who took placebo (p = 0.03); this effect was not observed in cognitively intact subjects (p = 0.39).. There is no clear benefit for ChEI therapy as an adjunct to antidepressant therapy for depressed older adults.

Topics: Antidepressive Agents; Cholinesterase Inhibitors; Cognition Disorders; Depression; Donepezil; Drug Therapy, Combination; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine

Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement.. To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and cognitive impairment in Parkinson's disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease).. The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly.Reference lists of relevant studies were searched for additional trials.. Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson's disease (CIND-PD).. Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0.. Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000).For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001).For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial.For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01).For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03).For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms. The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Topics: Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Humans; Indans; Lewy Body Disease; Neuroprotective Agents; Parkinson Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Cognitive impairment occurs in up to one-third of intensive care patients and may affect one or more cognitive domains. Because data are scarce on therapies for this complication, prevention remains the prevailing strategy. In this review, we discuss the clinical approach to cognitive impairment after an intensive care unit (ICU) stay.

Topics: Cholinesterase Inhibitors; Cognition; Cognition Disorders; Cognitive Behavioral Therapy; Critical Illness; Donepezil; Dopamine Uptake Inhibitors; Humans; Indans; Intensive Care Units; Methylphenidate; Piperidines; Psychometrics; Survivors

It has been shown that, during several years preceding the diagnosis of Alzheimer's disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer's disease or dementia. During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer's disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer's disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer's disease.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Continuity of Patient Care; Donepezil; Humans; Indans; Memantine; Piperidines; Randomized Controlled Trials as Topic

Topics: Animals; Biomarkers; Brain Neoplasms; Cholinesterase Inhibitors; Cognition Disorders; Cytokines; Donepezil; Humans; Hyperbaric Oxygenation; Indans; Magnetic Resonance Imaging; Neuropsychological Tests; Oxidative Stress; Piperidines; Radiosurgery; Radiotherapy; Radiotherapy, Conformal

Numerous patient- and disease-related factors increase the risk of rapid cognitive decline in patients with Alzheimer's disease (AD). The ability of pharmacological treatment to attenuate this risk remains undefined.. Pooled data from 14 randomized clinical studies of donepezil in the treatment of AD (N = 3748) were analyzed to identify predictors of fast decline and determine the effect of donepezil on the risk of fast decline.. Young age and more severe baseline cognitive, global, or behavioral status were identified as independent predictors of faster decline in placebo-treated patients. Multivariate models indicated that donepezil treatment was associated with a 39% to 63% reduction in the risk of faster decline.. These results correspond with previous findings, indicating relationships between age or baseline disease severity and rates of cognitive decline. Furthermore, they suggest that symptomatic therapy for AD could reduce the likelihood of faster decline in treated patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Female; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Piperidines; Predictive Value of Tests; Prognosis; Randomized Controlled Trials as Topic; Risk Factors

Topics: Aged; Antipsychotic Agents; Cerebral Ventricles; Cholinesterase Inhibitors; Cognition Disorders; Corpus Callosum; Delusions; Diagnosis, Differential; Donepezil; Female; Humans; Hydrocephalus, Normal Pressure; Indans; Magnetic Resonance Imaging; Memantine; Piperidines; Severity of Illness Index; Sexual Behavior; Spouses; Ventriculoperitoneal Shunt

Topics: Animals; Antidepressive Agents, Second-Generation; Cognition Disorders; Dopamine D2 Receptor Antagonists; Double-Blind Method; Drug Discovery; Drug-Related Side Effects and Adverse Reactions; Humans; Piperazines; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Patients with schizophrenia suffer from cognitive deficits which are important predictors of functional outcome. Alterations such as reduced muscarinic and nicotinic receptors in the central cholinergic system in patients with schizophrenia may contribute to these cognitive impairments. Because such deficits do not respond to neuroleptic treatment, different approaches have been developed regarding pharmacological treatments that enhance central cholinergic transmission, e.g. with acetylcholinesterase inhibitors. In this review the pathophysiology of cognitive impairment in schizophrenia, results of studies using acetylcholinesterase inhibitors (donepezil, rivastigmine, physostigmine, and galantamine), and future research strategies are presented. Till now randomized, placebo-controlled studies exist only for donepezil and rivastigmine, and none could replicate the positive results of previous trials with open designs. More trials with higher numbers of patients are needed, particularly for substances with more complex mechanisms of action (e.g. galantamine).

Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Physostigmine; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Cannabis has been used throughout human history. Delta (9)-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. THC metabolises to 11-OH-THC and further to THC-acid, which is an inactive metabolite. We present an overview of the pharmacokinetics and pharmacodynamics of cannabinoids.. This article is based on selected literature with an emphasis on the pharmacodynamics of cannabinoids.. It has been demonstrated that mammalian tissues express cannabinoid receptors (CB1, CB2 and most probably CB3) and endogenous ligands for these. Knowledge of these receptors has lead to the development of components that stimulate (CB-agonists) or block their function (CB-antagonists). This opens up for the study of any potential therapeutic effects of cannabinoids. Research on a possible therapeutic potential of cannabinoids should however not overshadow the well-documented negative effects of cannabis; i.e. impaired cognitive functions, intoxication and an increased risk for development of psychosis and psychotic symptoms.

Topics: Cannabinoid Receptor Antagonists; Cannabinoids; Cannabis; Cognition Disorders; Dronabinol; Humans; Piperidines; Psychoses, Substance-Induced; Psychotropic Drugs; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Risk Factors

With the projected dramatic increase in the number of people who will be diagnosed with Alzheimer's disease (AD) in the coming years, interest is growing in identifying and treating adults at high risk for developing the disorder. Recent research suggests that individuals who will go on to receive a diagnosis of AD exhibit deficits in cognitive performance years beforehand. Those with mild cognitive impairment (MCI), for example, have characteristic cognitive deficits, such as memory loss, and convert to a diagnosis of AD at a faster rate than cognitively healthy controls. MCI has thus become a focus of research because it may help identify high-risk individuals for whom prophylactic treatments designed to slow the progress toward AD can be prescribed. After describing the diagnostic criteria and dementia outcomes associated with MCI, this article discusses several challenges to the study of cognitive impairment before the diagnosis of AD.

Topics: Adult; Alzheimer Disease; Cognition Disorders; Disease Progression; Donepezil; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Assessment; Time Factors; Vitamin E

Topics: Alzheimer Disease; Antipsychotic Agents; Behavioral Symptoms; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Memantine; Piperidines; Receptors, N-Methyl-D-Aspartate

Accurate diagnosis of vascular cognitive impairment (VCI) is important but may be difficult. VCI diagnoses depend on determinations of the presence of both cognitive impairment and cerebrovascular disease (CVD), temporal causal links between cognitive impairment and CVD, and the presence or absence of other potential contributors to cognitive impairment, such as Alzheimer's disease (AD). Diagnostic criteria differ across currently utilized systems, resulting in widely differing VCI prevalence rates. Also, current systems may not be able to differentiate "pure" VCI from "mixed" AD and CVD. National Institute of Neurological Disorders and Stroke harmonization criteria for VCI have been developed for study and validation to help bridge gaps in our understanding of VCI diagnosis. VCI management begins with atherogenic risk factor control. Current VCI treatment options demonstrate statistical improvement but not consistent global clinical efficacy. Future clinical trials should concentrate on both primary risk factor control and development of new therapeutic agents to treat patients already diagnosed with VCI.

Topics: Central Nervous System Agents; Clinical Trials as Topic; Cognition Disorders; Dementia, Vascular; Donepezil; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Risk Factors; Rivastigmine

Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.

Topics: Aged; Alzheimer Disease; Anti-Inflammatory Agents; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Lactones; Neuropsychological Tests; Phenylcarbamates; Piperidines; Rivastigmine; Severity of Illness Index; Sulfones; Vitamin E

Ampakines are a structurally diverse family of small molecules that positively modulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, and thereby enhance fast, excitatory transmission throughout the brain. Surprisingly, ampakines have discrete effects on brain activity and behavior. Because their excitatory synaptic targets mediate communication between cortical regions, serve as sites of memory encoding, and regulate the production of growth factors, ampakines have a broad range of potential therapeutic applications. Several of these possibilities have been tested with positive results in preclinical models; preliminary clinical work has also been encouraging.

Topics: Animals; Brain; Cognition Disorders; Dioxoles; Drug Evaluation, Preclinical; Excitatory Amino Acid Agonists; Humans; Memory; Mental Disorders; Nerve Growth Factors; Oxazines; Piperidines; Protein Conformation; Receptors, AMPA

Diabetes mellitus and cognitive decline are major public health concerns among the elderly. In diabetic subjects without dementia, certain cognitive domains are impaired, such as memory, attention, and executive/frontal lobe function (diabetic cognitive dysfunction). Recent epidemiological studies have suggested that diabetes increases the risks for vascular dementia as well as Alzheimer's disease. There are accumulating evidences that indicate biological linkage between impaired brain glucose metabolism homeostasis and cognitive decline. Diabetes may cause serious brain damages through several mechanisms and induce a variety of cognitive decline. Most critical issue to be resolved is to identify the mechanism of dementia leading from diabetic cognitive dysfunction. Once elderly diabetics had severe cognitive decline, effective treatment of diabetes were hardly obtained. Thus, diabetic cognitive decline should be considered as an important comorbidity of the elderly diabetes and long-term management of hyperglycemia is required from a view point to sustain healthy brain function. In this short review, we are summarizing the clinical features and current biological findings of diabetic cognitive decline. Also, we introduce the comprehensive treatment of demented diabetic elderly, including therapeutic strategy, nursing and care.

Topics: Aged; Antihypertensive Agents; Brain; Cognition Disorders; Dementia; Diabetes Mellitus, Type 2; Donepezil; Glucose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Hyperlipidemias; Hypertension; Indans; Piperidines; Risk; Risk Factors

Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors.. The objective of this review is to assess whether donepezil improves the well-being of patients with dementia due to Alzheimer's disease.. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' and 'Aricept' on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. Members of the Donepezil Study Group and Eisai Inc were contacted.. All unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with mild, moderate or severe dementia due to Alzheimer's disease.. Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated.. 23 trials are included, involving 5272 participants. Most trials were of 6 months or less duration in selected patients. Available outcome data cover domains including cognitive function, activities of daily living, behaviour , global clinical state and health care resource costs. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared with placebo on the ADAS-Cog scale (-2.01 points MD, 95%CI -2.69 to -1.34, p<0.00001); -2.80 points, MD 95% CI -3.74 to -2.10, p<0.00001) and for 10 mg/day donepezil compared with placebo at 52 weeks (1.84 MMSE points, 95% CI, 0.53 to 3.15, p=0.006). The results show some improvement in global clinical state (assessed by a clinician) in people treated with 5 and 10 mg/day of donepezil compared with placebo at 24 weeks for the number of patients showing improvement or no change (OR 2.18, 95% CI 1.53 to 3.11, p=<0.0001, OR 2.38, 95% CI 1.78 to 3.19, p<0.00001). Benefits of treatment were also seen on measures of activities of daily living and behaviour, but not on the quality of life score . There were significantly more withdrawals before the end of treatment from the 10 mg/day (but not the 5 mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10 mg/day. Benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose. Two studies presented results for health resource use, and the associated costs. There were no significant differences between treatment and placebo for any item, the cost of any item, and for the total costs, and total costs including the informal carer costs. A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea, muscle cramps, dizziness, fatigue and anorexia (significant risk associated with treatment) in the 10 mg/day group compared with placebo but very few patients left a trial as a direct result of the intervention.. People with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with donepezil experienced benefits in cognitive function, activities of daily living and behaviour. Study clinicians rated global clinical state more positively in treated patients, and measured less decline in measures of global disease severity. There is some evidence that use of donepezil is neither more nor less expensive compared with placebo when assessing total health care resource costs. Benefits on the 10 mg/day dose were marginally larger than on the 5 mg/day dose. Taking into consideration the better tolerability of the 5 mg/day donepezil compared with the 10 mg/day dose, together with the lower cost, the lower dose may be the better option. The debate on whether donepezil is effective continues despite the evidence of efficacy from the clinical studies because the treatment effects are small and are not always apparent in practice .

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

In the last decade much attention has been paid to the development of metabolically non-reversible dimeric or hybrid compounds, which combine two structural units of one or two lead compounds of interest for the treatment of Alzheimer's disease. As a consequence of their capability to simultaneously interact with two binding sites of the same biological target (the enzyme acetylcholinesterase in most cases), to expand their interaction in the main binding site of the target molecule, or to interact with two different biological targets of interest in the pathogenesis of the disease, these dimeric or hybrid compounds exhibit an improved pharmacological profile including high affinity interactions, additional non conventional actions or complementary actions, what makes them potential drug candidates for the treatment of Alzheimer's disease. Herein, we review from a structural point of view the main classes of dimeric or hybrid compounds developed for the treatment of Alzheimer's disease, along with the pharmacological profile of the most active compounds.

Topics: Alzheimer Disease; Aminoquinolines; Animals; Binding Sites; Cholinesterase Inhibitors; Cognition Disorders; Heterocyclic Compounds, 4 or More Rings; Humans; Monoamine Oxidase Inhibitors; Piperidines; Structure-Activity Relationship; Tacrine

Alzheimer's disease (AD) prevalence rates in the United States are expected to triple over the next 50 years, a consequence of the overall aging of the U.S. population. Because of the profound and far-reaching impact of AD, this projected increase in prevalence is expected to pose a tremendous challenge. Alzheimer's disease results in the cognitive and functional deterioration of the affected patient, and behavioral disturbances frequently accompany the disease. Furthermore, because of its progressive and debilitating nature, AD takes a dramatic emotional, physical, and financial toll on the patient's primary caregiver. Nonetheless, despite the burden experienced by both patients and caregivers, strategies for minimizing the negative consequences of AD are well characterized. Central to the successful management of AD is the prompt and accurate diagnosis of the disease, with current guidelines calling for a 2-tiered approach in which patients first undergo screening using a brief cognitive assessment tool, followed by a comprehensive battery of physical, psychological, and neurologic tests if signs of possible cognitive impairment are evident upon screening. Once a conclusive diagnosis of AD has been made, the development of a disease management approach targeting the needs of the patient and his or her caregiver becomes a primary concern. Pharmacologic interventions may play an important role in such approaches, as agents such as cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine have been associated with favorable outcomes for patients and caregivers alike. However, in addition to the therapeutic benefits of these agents, associated side effects and potential drug-drug interactions must also factor into decisions regarding the pharmacologic treatment of AD.

Topics: Aged; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Mass Screening; Memantine; Middle Aged; Neurologic Examination; Neuropsychological Tests; Patient Care Management; Physical Examination; Piperidines; Practice Guidelines as Topic; Prevalence; Randomized Controlled Trials as Topic; Severity of Illness Index; Stress, Psychological; Treatment Outcome

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Memory; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Aged; Aged, 80 and over; Amantadine; Cerebral Infarction; Cholinergic Antagonists; Cognition Disorders; Deamino Arginine Vasopressin; Diagnosis, Differential; Donepezil; Humans; Indans; Levodopa; Piperidines; Quality of Life; Serotonin Agents; Urination Disorders

In schizophrenia, cognitive dysfunctions commonly affect attention, memory and executive function, interfere with functional outcome and remain difficult to treat. Previous studies have implicated the cholinergic system in cognitive functioning. In Alzheimer's disease, cholinergic agonists have shown modest clinical benefits on cognitive and behavioural symptoms. Impaired cholinergic activity might also be involved in schizophrenia. Hence the role of cholinesterase inhibitors (ChEI) as adjunctive therapy is under study. We aimed to review the literature and evaluate the overall effectiveness of ChEI adjunctive therapy for the management of cognitive dysfunctions in schizophrenia.. We conducted a computer-based search using PubMed (up to February 15, 2006) and ISI Web of Science (conference proceeding abstracts from January 2003 to December 2005) databases. We used the search terms "schizophrenia," "cognition or memory" and "tacrine or donepezil or rivastigmine or galantamine." Studies included were critically analyzed for allocation, blindness, duration and study design, demographic data, and clinical and neuropsychological outcome assessments. We excluded studies that involved patients with psychiatric disorders other than schizophrenia-spectrum or if they involved animals or molecular investigations. We also excluded conference proceeding abstracts with no explicit neuropsychological battery and/or results.. Data on ChEI as adjunctive therapy for the cognitive impairments in schizophrenia are sparse and so far derived from small samples and mostly open uncontrolled studies. ChEI's potential in long-term management has barely been documented and remains to be fully explored.. There is insufficient evidence on whether ChEI should be used for the treatment of cognitive dysfunctions in schizophrenia. Nevertheless, further studies with appropriate trial designs and outcome measures in homogenous schizophrenia populations are warranted.

Topics: Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Schizophrenic Psychology; Treatment Outcome

Mild cognitive impairment (MCI) is a clinical syndrome thought to represent the transition between normal function and dementia. This review describes data that support the existence of such a transitional phase, outlines the heterogeneity of MCI and how that has influenced the evolving concept of MCI, and discusses the impact of heterogeneity on recent MCI clinical trials.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia; Donepezil; Humans; Indans; Models, Psychological; Neuropsychological Tests; Piperidines; Syndrome; Terminology as Topic; Treatment Outcome

This review was conducted in order to determine the efficacy of donepezil and galantamine in the treatment of cognitive symptoms of Alzheimer's disease, and also to determine whether galantamine was a superior pharmacological intervention. Meta-analytic methods were used to analyse the data from eight empirical studies which met the inclusion criteria specified. By finding the mean effect sizes of the treatment on the outcome measures of cognition, it was determined that neither drug was greatly efficacious. However, this result does not necessarily diminish the practical value of the drug. It was also found that galantamine was no better than donepezil at treating cognitive decline in AD.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Male; Nootropic Agents; Piperidines; Treatment Outcome

This article reviews the piperidine derivative, donepezil hydrochloride (E2020, Aricept), a reversible central acetylcholinesterase inhibitor currently approved for treatment of mild-to-moderate Alzheimer's disease. Donepezil is well absorbed orally, unaffected by food or by time of administration; it reaches therapeutic levels in doses of 5-10 mg/day and peak plasma concentrations are obtained 3-4 h after oral administration. A single bedtime dose is recommended due to the long elimination half-life of the drug (70 h). Donepezil does not cause liver toxicity or significant drug interactions and is relatively well-tolerated. Initial side effects include nausea, vomiting, diarrhoea, insomnia, muscle cramps, fatigue, anorexia and syncope. Caution is advised in patients with bradycardia. Long-term use of donepezil in AD has been found to delay nursing-home placement and to result in caregiver respite. Donepezil also slows deterioration of cognition and global function in patients with moderate-to-severe AD, with improvement of abnormal behaviours. In addition to AD, donepezil demonstrates significant improvement in cognition, global function and activities of daily living in comparison with placebo-treated patients with vascular dementia and has potential therapeutic benefit for other neurological conditions.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia, Vascular; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Piperidines; Psychiatric Status Rating Scales; Receptors, Cholinergic; Schizophrenia

Vascular disease is the second commonest cause of dementia after Alzheimer's disease. There are difficulties in classifying patients with this type of cognitive impairment owing to varied clinical presentation and different types of arterial disease. There is some degree of overlap in the neuropathology of Alzheimer's and vascular dementia. Deficient cholinergic neurotransmission, a characteristic of Alzheimer's disease, has been postulated to contribute to the cognitive impairment of vascular disease of the brain. Cholinesterase inhibitors, such as donepezil, may therefore be a rational treatment.. To assess the clinical efficacy and tolerability of donepezil on cognitive function, clinical global impression, activities of daily living and social functioning of people with vascular cognitive impairment.. Relevant randomized controlled trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Group Specialized Register on 21 July 2003 using the terms donepezil, E2020 and Aricept. This Register consists of records from all major healthcare databases and many ongoing trials databases. Unpublished trials were requested from the drug company Eisai Inc and they provided us with the required data.. All unconfounded randomized double-blind trials comparing donepezil with placebo were eligible for inclusion. Trials using combinations of donepezil with other pharmacological interventions were excluded.. Both reviewers assessed studies against the criteria for inclusion and extracted data. Data were pooled where appropriate, and weighted mean differences or Peto odds ratios with 95% confidence intervals calculated. Intention-to-treat analysis was undertaken when possible.. Two large-scale, randomized, double-blind, parallel-group controlled trials were identified for inclusion. A total of 1219 people with mild to moderate cognitive decline due to probable or possible vascular dementia (according to the NINCDS/AIREN criteria and the Hachinski Ischemia Scale) were recruited. Donepezil, at doses of 5 or 10 mg a day was compared with placebo for 24 weeks. For each outcome measure, mean change from baseline at weeks 12 and 24, using a last observation carried forward analysis, was calculated. Cognitive function: The donepezil groups showed statistically significantly better performance than the placebo groups on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) at 12 and 24 weeks. The donepezil groups produced statistically significantly better scores than the placebo groups on the Mini-Mental State Examination (MMSE) at 12 and 24 weeks. Global function: The sum of the boxes of the Clinical Dementia Rating (CDR-SB) showed at 24 weeks a statistically significant benefit of 10 mg donepezil daily over both placebo and a 5 mg daily dosage. The Clinician's Interview-Based Impression of Change-plus version (CIBIC-plus) showed improved global function of participants taking 5 mg of donepezil daily compared with the placebo group but this was not seen in the higher dose group. Activities of daily living and social behaviour: On the Instrumental Activity of Daily Living (IADL) scale, there was no statistically significant difference between the groups taking donepezil 5mg per day donepezil and placebo, but the group taking 10 mg of donepezil a day showed benefit compared with placebo There were statistically significant benefit for donepezil at either dosage compared with placebo on the Alzheimer's Disease Functional Assessment and Change Scale (ADFACS). Tolerability and adverse effects: Broad range of adverse events were reported in the studies and data confirmed that donepezil was well tolerated, and most of the side effects were transient and were resolved by stopping the medication. Some of these events, especially nausea, diarrhoea, anorexia and cramp appeared more frequently on the 10 mg dose where there was a statistically significant difference compared with placebo. Drop-out: The drop-out rate was similar between the groups, 84.2% (330) patients completed the studies. The withdrawal rate was low and due mainly to side effects.. Evidence from the available studies support the benefit of donepezil in improving cognition function, clinical global impression and activities of daily living in patients with probable or possible mild to moderate vascular cognitive impairment after 6 months treatment. Extending studies for longer periods would be desirable to establish the efficacy of donepezil in patients with advanced stages of cognitive impairment. Moreover, there is an urgent need for establishing specific clinical diagnostic criteria and rating scales for vascular cognitive impairment.

Topics: Activities of Daily Living; Cognition Disorders; Dementia, Vascular; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMP

Topics: Adult; Aged; Animals; Benzothiadiazines; Brain-Derived Neurotrophic Factor; Cognition Disorders; Depressive Disorder; Excitatory Amino Acid Agonists; Humans; Neuronal Plasticity; Parkinson Disease; Piperidines; Pyrrolidinones; Receptors, AMPA

The present review described the effects of acetylcholinesterase (AChE) inhibition on the cerebral cholinergic neuronal system in the conscious monkey brains with PET. Somatosensory stimulation induced a regional cerebral blood flow (rCBF) response, revealed with [(15)O]H(2)O, in the contralateral somatosensory cortex. Scopolamine resulted in an abolished rCBF response to stimulation, and this abolished rCBF response was recovered by physostigmine, donepezil, and tacrine. Donepezil suppressed AChE activity, analyzed by [(11)C]MP4A, in all cortical regions in a dose-dependent manner. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex as measured by microdialysis. Binding of [(11)C](+)3-PPB to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [(11)C](+)3-PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition by donepezil. These results demonstrated that PET imaging with specifically labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful tool for pre-clinical evaluation of novel drugs.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Frontal Lobe; Haplorhini; Humans; Indans; Memory; Microdialysis; Piperidines; Positron-Emission Tomography

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Piperidines

Dementia with Lewy bodies (DLB) is a common cause of dementia with effects on cognition, mood, behavior, and function. Changes in the acetylcholine system have been reported in brains of patients with DLB, which provides a rationale for trials of acetylcholinesterase inhibitors in DLB. This review includes all English-language publications found via Medline and related to the efficacy and/or safety of these compounds in DLB. Preliminary data suggest that these compounds may be efficacious in DLB and that future randomized clinical trials are strongly needed. Methodological limitations of the existing data include small sample sizes, and the paucity of standardized psychometric measures.

Topics: Aged; Basal Ganglia Diseases; Behavior; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition; Cognition Disorders; Donepezil; Humans; Indans; Lewy Body Disease; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Tacrine

Alzheimer's disease is common, incurable and disabling. It is expected to grow dramatically in prevalence over the next 50 years. At current, the standard of care for patients with mild and moderately severe Alzheimer's disease includes the use of acetylcholinesterase inhibitors. Donepezil (Aricept) is a highly selective acetylcholinesterase inhibitors with a pharmacokinetic profile allowing once-daily dosing. There is an extensive knowledge base derived from published clinical trials of donepezil in Alzheimer's disease, revealing consistent efficacy in cognition, global clinical ratings and daily function. Donepezil is also associated with additional meaningful outcomes such as reduced risk for, or delay to, nursing home placement. Despite a sense of limited efficacy of this drug class among prescribers, number needed-to-treat analyses suggest donepezil is highly effective at reducing the long-term adverse outcomes associated with Alzheimer's disease.

Topics: Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia; Diarrhea; Donepezil; Drug Interactions; Humans; Indans; Nausea; Piperidines; Treatment Outcome; Vomiting

Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors. However, some (like tacrine) are associated with adverse effects such as hepatotoxicity, but donepezil (E2020, Aricept) is safer.. The objective of this review is to assess whether donepezil improves the well-being of patients with dementia due to Alzheimer's disease.. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' and 'Aricept' on 9 October 2002. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. Members of the Donepezil Study Group and Eisai Inc were contacted.. All unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with mild, moderate or severe dementia due to Alzheimer's disease.. Data were extracted by one reviewer (JSB ), pooled where appropriate and possible, and the weighted mean differences or Peto odds ratios (95%CI) estimated.. Sixteen trials are included, involving 4365 participants. The trials were of 12, 24 or 52 weeks duration in selected patients. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are unavailable. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared with placebo (-2.02 points on the ADAS-Cog scale WMD, 95%CI -2.77 to -1.26, p<0.00001; -2.92 points on the ADAS-Cog scale WMD 95% CI -3.74 to -2.10, p<0.00001)and for 10 mg/day donepezil compared with placebo at 52 weeks (1.84MMSE points, 95% CI, 0.53 to3.15, p=0.006). The results show some improvement in global clinical state (assessed by an independent clinician) in people treated with 5 and 10 mg/day of donepezil compared with placebo at 12 and 24 weeks. Benefits of treatment were also seen on measures of activities of daily living and behaviour. There were significantly more withdrawals before the end of treatment from the 10 mg/day (but not the 5 mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10 mg/day.A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea and anorexia in the 10 mg/day group compared with placebo and the 5 mg/day group, but very few patients left a trial as a direct result of the intervention.. People with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with donepezil experienced benefits in cognitive function, activities of daily living and behaviour. Study clinicians rated global clinical state more positively in treated patients, and measured less decline in measures of global disease severity. Although no significant changes were measured on a patient-rated quality of life scales, the instrument used was crude and possibly unsuited to the task. The additional data now available confirm the findings of the previous issue of this review and extend the evidence for the effectiveness of treatment to at least 52 weeks and to those with severe dementia. More evidence is still needed for the economic efficacy of donepezil, but clinical efficacy is confirmed.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic

The current recommended standard of care for the symptomatic treatment of mild to moderate Alzheimer's disease is cholinesterase inhibitors. In short- and long-term studies, the 3 cholinesterase inhibitors most commonly used, donepezil, rivastigmine, and galantamine, have demonstrated efficacy in improving not only cognition but also function and behavior in patients suffering from mild to severe cases of Alzheimer's disease and other forms of dementia. However, the benefits of cholinesterase inhibitors in treating the broad spectrum of symptoms associated with Alzheimer's disease are not sustained indefinitely, and the illness continues to progress even while patients are receiving treatment. Additionally, while temporary stabilization may occur, there is typically only a modest improvement from baseline, and side effects from treatment with cholinesterase inhibitors can be too severe for some patients to tolerate. Therefore, additional therapies for Alzheimer's disease still need to be developed that include more tolerable agents with alternative mechanisms of action and broader efficacy.

Topics: Alzheimer Disease; Behavioral Symptoms; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Multicenter Studies as Topic; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

Mild Cognitive Impairment (MCI) is an emerging concept used to describe memory decline and probably attention disturbances in otherwise intellectually intact individuals. MCI may be considered in 12 to 15 p. 100 of the cases as announcing an Alzheimer's Disease (AD). Although still speculative, the debate concerning the drugs susceptible to normalize symptoms of MCI or to stop conversion to AD must be raised. For that purpose, several long term clinical trials are running (antioxidants, nootropics, anticholinesterasics.) and new molecules in the pipe-line should be assessed in patients with the diagnosis of MCI.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dopamine Agonists; Humans; Indans; Neuropsychological Tests; Piperidines; Severity of Illness Index; Vitamin E

Topics: Alzheimer Disease; Clinical Trials as Topic; Cognition Disorders; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

The number of patients with Alzheimer's disease (AD) and related dementia treated in managed care organizations (MCOs) is increasing, and this trend is expected to continue. Therefore, it is critical that MCOs develop disease management strategies for this population.. To review the literature on the prevalence, costs, and treatment of AD and related dementia.. Review of published articles from MEDLINE and peer-reviewed journals.. Prevalence of AD and related dementia is approximately 5.7% among those aged 65 and older. Prevalence data from claims-based studies of AD in managed care are lower, ranging from 0.55% to 0.83%. Costs for formal care average $27,672 per patient annually, with long-term care being the most costly component. Annual costs for informal care are estimated to be $10,400 to $34,517 per patient. Additional costs associated with AD include lost wages and productivity of patients and caregivers and costs associated with increased morbidity of caregivers. Donepezil treatment is well tolerated and has been extensively tested and evaluated in clinical settings. Early diagnosis and treatment of AD with donepezil has been shown to slow cognitive decline in AD. Although study findings regarding the cost offsets of donepezil-treated patients to date are mixed, there is a growing body of evidence to support the inclusion of this and other therapies into an MCO's AD treatment armamentarium.. It is unlikely that MCOs will escape the increased prevalence and costs associated with AD. Opportunities exist through patient management programs targeted toward early diagnosis, effective use of medications, control of comorbidities, and patient and family support to partially offset these costs while providing quality patient care.

Topics: Aged; Alzheimer Disease; Cognition Disorders; Cost of Illness; Donepezil; Female; Humans; Indans; Male; Managed Care Programs; Medicaid; Nootropic Agents; Piperidines; Prevalence; United States

Alzheimer's disease is the most common cause of dementia and is a primary degenerative disease of the brain of unknown cause. Onset is usually late in life with increasing impairment of memory, developing gradually into a global impairment of cognition, orientation, linguistic ability and judgement. The clinical course is accompanied by growing disability and dependency on care. One of the characteristic features of the disease is the widely variable rate of progression seen in different patients. Acetylcholine is an important neurotransmitter associated with memory, and abnormalities in cholinergic neurones (including cell loss) are among the many neurological and neurochemical abnormalities that develop in AD. One approach to lessening the impact of these abnormalities is to inhibit the breakdown of acetylcholine by blocking the relevant enzyme. Tacrine was the first compound approved as a treatment for AD in the US and worked in this way, but caused severe side effects. E2020 (donepezil, Aricept) is a second generation cholinesterase inhibitor and appears to be highly specific, with relatively few side effects.. The objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease.. The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'donepezil', 'E2020' and 'ARICEPT'. Medline, PsychLIT and EMBASE electronic databases were searched with the above terms. Members of the Donepezil Study Group and Eisai Inc were contacted.. All unconfounded, double-blind, randomised controlled trials in which treatment with donepezil was administered for more than a day and compared with placebo in patients with Alzheimer's disease.. Data were extracted independently by the reviewers (JSB & DB), pooled where appropriate and possible, and the weighted or standardised mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat data were used.. There are 4 included trials, covering treatment of 12 or 24 weeks duration in highly selected patients. The only information available on one trial (Gauthier 1998) is a conference abstract which reports no usable results. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. The results of three trials suggest a small beneficial effect of donepezil in improving cognitive function: at a 5mg/day dose, improvements measured -2.6 points (95%CI -3.5 -- -1.8) on weighted mean difference, in the midrange of the 70 point ADAS-Cog scale. The results of two trials show some improvement in global clinical state (assessed by an independent clinician) in those treated with donepezil compared to placebo. The patient's own rating of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/d (but not the 5mg/d) donepezil group compared with placebo, which may have resulted in some overestimation of beneficial changes at 10mg/d in progressively declining characteristics, as last available measures were used in analyses. A variety of adverse effects were recorded, but very few patients left a trial as a direct result of the intervention.. In selected patients with mild or moderate Alzheimer's disease treated for periods of 12 or 24 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Piperidines

Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors. However, some (like tacrine) are associated with adverse effects such as hepatotoxicity, but E2020 (donepezil, Aricept) is thought to be more specific in its action, and safer.. The objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease.. The Cochrane Dementia and Cognitive Improvement Group specialized register was searched using the terms 'donepezil', 'E2020' and 'Aricept'. Members of the Donepezil Study Group and Eisai Inc were contacted.. All unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with Alzheimer's disease.. Data were extracted by one reviewer (JSB ), pooled where appropriate and possible, and the weighted mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat (ITT) data were used.. Eight trials are included, involving 2664 participants. The trials were of 12, 24 or 52 weeks duration in selected patients. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared to placebo (1.9 points on the ADAS-Cog scale, WMD 1.86, 95%CI -2.60 to -1.11; 2.9 points on the ADAS-Cog scale, WMD -2.91, 95% CI -3.65 to -2.16)and for 10mg/day donepezil compared to placebo at 52 weeks (1.7 MMSE points, 95% CI, -2.59 to -0.82). The results of three studies show some improvement in global clinical state (assessed by an independent clinician) in those treated with 5 and 10mg/day of donepezil compared with placebo at 12 and 24 weeks. The patients' own ratings of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/day (but not the 5mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10mg/day A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea and anorexia in the 10mg/day group compared with placebo and the 5mg/day group, but very few patients left a trial as a direct result of the intervention.. In selected patients with mild or moderate Alzheimer's disease treated for periods of 12, 24 or 52 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Humans; Indans; Piperidines; Randomized Controlled Trials as Topic

The rapid growth of the world's Alzheimer's disease (AD) population has resulted in a tremendous financial burden on society, a situation exacerbated by the fact that the funding of health and social services faces increasing restrictions in the coming years. As a consequence, several cost-of-illness studies, aimed at assessing the total costs associated with the care of an AD patient or with individual components thereof, have been conducted, with a view to identifying areas in which costs might be reduced. For example, the Costs of Dementia (CoDem) study, described here, aims to give a profile of the total economic costs of AD in Italy. While this study found the number of Instrumental Activities of Daily Living lost to be the principal predictor of the weekly costs for home care, other studies have reported a correlation between total cost and Mini-Mental State Examination (MMSE) score. The basis for a correlation between cost and disease severity is discussed. Pharmacoeconomics aims to assess the cost effectiveness of interventions that may form part of an overall management strategy in AD. As institutionalization is the largest cost element in the care of any AD patient, efforts at cost containment have focused on maintaining patients at home for as long as possible. The results of studies on a number of interventions, namely, screening, reality orientation therapy, special care units, family interventions, and drug treatment, are discussed, although the costs and, indeed, the long-term benefits associated with many of these remain unknown. Although information concerning costs is essential in health resource allocation, it is also vital that meaningful ways in which to assess quality-of-life issues be developed as the basis for genuine cost-benefit judgments.

Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Combined Modality Therapy; Cost of Illness; Costs and Cost Analysis; Donepezil; Humans; Indans; Institutionalization; Italy; Mental Health Services; Neuropsychological Tests; Piperidines; Reality Therapy; Tacrine

Regulatory guidelines in the US and Europe generally require that a drug specifically indicated for treating Alzheimer's disease (AD) must demonstrate an effect upon the core manifestations of dementia. Progressive cognitive and functional losses are the cardinal features of AD. In the US, current guidelines require that new AD treatments show effectiveness on performance-based measures of cognition and on clinician-rated global assessments. Improvement in function is also emphasized in the European guidelines. The primary instruments that have been used to evaluate changes in cognition and global function in most recent AD trials are the cognitive subscale of the Alzheimer's Disease Assessment Scale and a version of the Clinician's Interview Based Impression of Change, respectively. The results from three pivotal trials investigating the acetylcholinesterase inhibitor, donepezil, are used to demonstrate the way in which these tools are used, how to interpret the data they provide, and to determine their overall value in ascertaining efficacy in clinical practice.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Guidelines as Topic; Humans; Indans; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

This article combines data from a clinical trial of donepezil with costing figures to evaluate expected direct costs of care over 5 years after diagnosis of Alzheimer's disease (AD) for patients aged 75 years and over at diagnosis. A Markov model simulates the progression of elderly persons through changing levels of severity. The model compares three treatment regimes for each of two patient groups; mild AD at start of treatment; moderate AD at start of treatment. Patients are followed until 5 years after the start of the treatment. Despite the acquisition costs, use of donepezil is approximately cost-neutral for both 5 mg and 10 mg treatment groups and for patients initially at either mild or moderate states of illness. Expected costs are slightly higher than for the placebo group, but higher expenditure on drugs is partly offset by lower costs of care consequent on treated patients not declining as rapidly as those untreated. The model showed that donepezil patients spent less time in the state of severe dementia, where costs of care are higher. Sensitivity analysis on key assumptions demonstrated that expected costs were highly dependent on discount rate and, more significantly, on the mortality rate.

Topics: Aged; Alzheimer Disease; Cognition Disorders; Cost-Benefit Analysis; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Markov Chains; Models, Economic; Models, Neurological; Models, Psychological; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome; United Kingdom

This article reviews placebo-controlled studies addressing drug efficacy for the cognitive deficits of Alzheimer's disease. Efforts to compensate for the presynaptic cholinergic deficiency in Alzheimer's disease by pharmacologically inhibiting acetylcholine degradation have been successful in several clinical trials. Two cholinesterase inhibitors are available for Alzheimer's disease, and others most likely will soon be available. Cholinesterase inhibitors represent the only therapy currently approved for the treatment of Alzheimer's disease. The antioxidant drugs alpha-tocopherol (vitamin E) and selegiline have been demonstrated marginally superior to placebo for slowing functional deterioration in patients with moderately advanced Alzheimer's disease. Epidemiologic studies suggest protective effects against Alzheimer's disease from postmenopausal estrogen replacement and nonsteroidal anti-inflammatory drugs. Placebo-controlled studies prospectively evaluating the hypotheses generated by these epidemiologic studies are ongoing.

Topics: Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Estrogen Replacement Therapy; Humans; Indans; Nootropic Agents; Piperidines; Placebos; Tacrine; Treatment Outcome; Trichlorfon

Therapeutic approaches to the cognitive impairment of dementia are making their way into clinical practice. Clinical pharmacologic approaches toward improvement of cognitive symptoms are discussed, with an emphasis on cholinergic approaches, since they currently appear most promising and since several cholinesterase inhibitors may soon be available for prescribing. As more knowledge is gained about dosing, side effects, and mechanisms of action, these drugs can be prescribed more efficiently. Current research approaches to slowing the rate of cognitive decline are discussed, including the use of antioxidants, monoamine oxidase-B inhibitors, and cholinesterase inhibitors. Drugs that improve cognition may also have effects on behavioral symptoms, severe dementia, and non-Alzheimer's dementia. Evidence suggests that some dementia patients may be particularly responsive to intervention and that other medications may enhance response. Psychosocial interventions may also contribute to prolonging the time to institutionalization.

Topics: Aged; Alzheimer Disease; Antioxidants; Carbamates; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Humans; Indans; Monoamine Oxidase Inhibitors; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine; Trichlorfon

Recent clinical trials of donepezil and vitamin E have produced active therapeutic drugs for the treatment of patients with Alzheimer disease (AD). The AD research community is now in a gray zone between the absence of accepted therapies and the presence of completely effective therapies. How should these therapies guide the choice of the proper control for future AD clinical trials? The community equipoise principle can guide a process to answer this question. The principle is that a clinical trial should answer clinical questions that are valued by the community who will use the results of that trial. This means that the choice of the proper control for future AD clinical trials ought to be guided by the values of a community who will experience the results of those trials: physicians and patients or their representatives such as caregivers. The values of patients can be included by giving them a voice in the design and review of clinical trials. Community dialogue should be the norm for the design and review of AD clinical trials. We conclude with suggestions to foster this dialogue and issues that should be addressed.

Topics: Cognition Disorders; Control Groups; Controlled Clinical Trials as Topic; Donepezil; Ethics Committees, Research; Ethics, Medical; Federal Government; Government Regulation; Humans; Indans; Piperidines; Placebos; Research Design; Research Subjects; Risk Assessment; Therapeutic Human Experimentation; Vitamin E

Diabetes mellitus is a common disease in older people, with almost 50% of Type 2 diabetic patients being over 60 years of age; despite this, half of older people with frank diabetes are not diagnosed. While insulin resistance is common in older people, large numbers also have impaired insulin secretion. Age, body habitus and physical activity all play a role in the pathogenesis of hyperglycaemia associated with diabetes mellitus. Leptin levels relate to insulin resistance in older people and amylin secretion is associated with delayed return of glucose levels to baseline. Depression, impaired cognitive function, and lack of recognition of thirst and subsequent dehydration are important factors to be taken into account in the management of older diabetic patients, who may also have impaired physical function, an increased rate of injurious falls, and increased prevalence of pressure ulcers, amputations and tuberculosis. Hyperglycaemia can result in a decreased pain threshold and incontinence. Dietary management plays less of a role in older diabetic patients but exercise, with a particular emphasis on balance and stability, is an important component of the management and treatment of older diabetic patients. The use of metformin as a treatment should be avoided in patients over 80 years of age because of declining kidney function. Insulin therapy is an option but as hypoglycaemia is related to advancing age, patients should be monitored carefully for the development of hypoglycaemia. Care providers also play an important role in the management of older people with diabetes mellitus. Glycaemic control can be obtained with minimal side-effects in most older diabetics including those patients in nursing homes.

Topics: Aged; Amyloid; Blood Glucose; Carbamates; Cognition Disorders; Depression; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Islet Amyloid Polypeptide; Male; Piperidines

Therapeutic approaches to treat the cognitive impairment in dementia and to treat slow decline are making their way into clinical practice. Cholinergic agents are currently the most promising treatment, and several cholinesterase inhibitors will soon be available for prescription. As physicians learn more about dosing, side effects, and mechanisms of action, they can prescribe these drugs more efficiently. Evidence suggests that certain patients with dementia may be particularly responsive to such intervention, and other medications may enhance response. Current experimental approaches to slowing the rate of cognitive decline include the use of antioxidants, monoamine oxidase-B inhibitors, cholinesterase inhibitors, and anti-inflammatory agents. Psychosocial interventions appear to help delay institutionalization. Drugs that improve cognition also may affect behavioral symptoms and severe dementia as well as non-Alzheimer dementia.

Topics: Alzheimer Disease; Antioxidants; Carbamates; Cholinergic Agents; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine; Trichlorfon

Clozapine has proved effective in alleviating a wide range of psychiatric symptoms in schizophrenia. Its effects on cognitive function in schizophrenia are more variable. Clozapine appears to have a salutary effect on some aspects of attention, response speed, and fluency, whereas it appears to have a mild but adverse effect on visual memory and some executive functions. This profile may be related to the affinity of clozapine for dopaminergic type I and muscarinic receptors and relative lack of affinity for dopaminergic type II receptors.

Topics: Clozapine; Cognition; Cognition Disorders; Dopamine; Humans; Isoxazoles; Neuropsychological Tests; Piperidines; Receptors, Dopamine; Receptors, Muscarinic; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clinical trials with muscarinic agonists or acetylcholine esterase inhibitors for the treatment of Alzheimer's dementia have shown disappointing or equivocal results. An alternative treatment of this disease is the development of drugs which enhance the release of acetylcholine. It is believed, that of the five muscarinic receptor subtypes so far identified in the brain, M2 receptors are located presynaptically in the cortex and hippocampus and upon stimulation inhibit the release of acetylcholine. Based on this hypothesis, we initiated a drug discovery program with the aim of identifying selective and centrally active M2 antagonists which are capable of enhancing cholinergic transmission. These efforts resulted in the successful design and synthesis of novel muscarinic antagonists able to cross the blood brain barrier. Moreover, these compounds show few peripheral effects and possess a superior M2 versus M1 selectivity. The prototype of this novel class of M2 selective compounds, BIBN 99, could be a valuable tool to test the hypothesis that lipophilic M2 antagonists show beneficial effects in the treatment of cognitive disorders.

Topics: Animals; Benzodiazepinones; Brain; CHO Cells; Cognition Disorders; Cricetinae; Dibenzazepines; Drug Design; Motor Activity; Parasympatholytics; Piperidines; Pirenzepine; Pyridines; Rats; Receptors, Muscarinic; Structure-Activity Relationship

Alcohol dependence (AD) is associated with a dysregulated mesolimbocortical dopamine system-a pathway which is also implicated in both reward and cognition. The monoamine stabilizer (-)-OSU6162 (OSU) is a novel pharmacological compound with the ability to reduce ethanol intake and ethanol seeking in long-term drinking rats as well as reducing alcohol craving in AD patients. Dopaminergic drugs can both impair and improve cognitive functions, and the aim of the current study was to investigate the effect of OSU treatment on cognitive functioning in AD patients.. In a randomized double-blind placebo-controlled study, 56 individuals with AD received 14 days of OSU or placebo treatment. Neuropsychological tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB®) and other tasks were used to evaluate treatment effect on executive function/impulsivity, working memory, attention, emotional recognition, and divergent thinking.. OSU treatment did not cause short-term cognitive side effects, further supporting the potential of OSU as a clinically feasible pharmacological treatment in AD patients. OSU treatment might improve future planning, verbal divergent thinking, and emotional recognition latency, which in turn may have a beneficial impact on alcohol use outcomes. Future studies are needed to confirm these preliminary findings.

Topics: Adult; Alcohol Drinking; Alcoholism; Attention; Cognition; Cognition Disorders; Craving; Dopamine; Dopamine Agents; Double-Blind Method; Emotions; Executive Function; Female; Humans; Impulsive Behavior; Male; Memory, Short-Term; Middle Aged; Piperidines; Reaction Time; Recognition, Psychology; Young Adult

PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms.. To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive-enhancing medications.. Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21-24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive-enhancing medications. The primary outcome measure was change in the PD-adapted Scale for the Assessment of Positive Symptoms.. Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; -6.62 vs. -0.91; P = 0.002) versus the cognitively unimpaired (n = 135; -5.50 vs. -3.23; p = 0.046) group. The comparable change was -6.04 versus -2.18 (P = 0.012) and -5.66 versus -3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive-enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive-enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors.. The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive-enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Cognition Disorders; Double-Blind Method; Female; Humans; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Parkinson Disease; Piperidines; Psychotic Disorders; Treatment Outcome; Urea

Only a few approved drugs are capable of alleviating the cognitive and behavioural symptoms of people living with Alzheimer's disease (AD). In recent years, however, the number of studies examining the clinical effects of herbal medicines on cognitive function in patients with AD has increased considerably. This study evaluated the long-term effects of a traditional Japanese medicine (Kampo medicine) known as ninjin'yoeito (NYT) on cognitive impairment and mood status in patients with AD over a 2-year period.. Twenty-three patients with mild-to-moderate probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria were included. Each participant had exhibited an insufficient response to treatment with donepezil alone before the start of the trial. Eleven patients received treatment with donepezil alone, and the remaining patients received a combined treatment of donepezil and NYT for 2 years. Patients were assessed by the Mini-Mental State Examination and the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version for cognitive function, and the Neuropsychiatric Inventory was used to evaluate the patients' mood status at baseline and every 6 months for 2 years.. The Mini-Mental State Examination results showed no significant differences between the two groups. Significant improvements were observed on the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version and the Neuropsychiatric Inventory depression scores of patients who received the combined therapy with donepezil and NYT (Alzheimer's Disease Assessment Scale-cognitive component-Japanese version, 12 months: P < 0.01, 18 months: P = 0.04, 24 months: P < 0.01; Neuropsychiatric Inventory depression, 6 months: P < 0.05, 24 months: P < 0.05).. A 2-year follow-up of patients receiving donepezil and NYT treatment showed an improved cognitive outcome and alleviation of AD-related depression.

Topics: Affect; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Depression; Donepezil; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Medicine, Kampo; Panax; Piperidines; Prospective Studies; Severity of Illness Index; Treatment Outcome

Some breast cancer survivors report cognitive difficulties greater than 1 year after chemotherapy. Acetylcholinesterase inhibitors (AChEI) may improve cognitive impairment. We conducted a randomized, placebo-controlled, pilot study to assess the feasibility of using the AChEI, donepezil, to improve subjective and objective measures of cognitive function in breast cancer survivors.. Women who received adjuvant chemotherapy 1-5 years prior with current cognitive dysfunction symptoms were randomized to 5 mg of donepezil/day vs placebo for 6 weeks and if tolerated 10 mg/day for 18 weeks for a total of 24 weeks. A battery of validated measures of attention, memory, language, visuomotor skills, processing speed, executive function, and motor dexterity and speed was administered at baseline and at 24 and 36 weeks. Subjective cognitive function, fatigue, sleep, mood, and health-related quality of life were evaluated at baseline and at 12, 24, and 36 weeks.. Sixty-two patients were enrolled, 76 % completed the study, self-reported compliance was 98 %, and toxicities were minimal. At the end of treatment, the donepezil group performed significantly better than the control group on two parameters of memory-the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall (p = 0.033) and HVLT-R Discrimination (p = 0.036). There were no significant differences on other cognitive variables or in subjective cognitive function or quality of life.. Accrual to this feasibility trial was robust, retention was good, compliance was excellent, and toxicities were minimal.. Randomized clinical trials in breast cancer survivors to improve cognitive dysfunction are feasible. A phase III trial testing the efficacy of donepezil is warranted given these pilot results.

Topics: Adult; Affect; Aged; Breast Neoplasms; Chemotherapy, Adjuvant; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Fatigue; Feasibility Studies; Female; Humans; Indans; Memory; Middle Aged; Pilot Projects; Piperidines; Quality of Life; Self Report; Survivors

Postoperative cognitive dysfunction (POCD) is a well-known complication after cardiac surgery and may cause permanent disabilities with severe consequences for quality of life. The objectives of this study were, first, to estimate the frequency of POCD after on-pump cardiac surgery in patients randomized to remifentanil- or sufentanil-based anesthesia and, second, to evaluate the association between POCD and quality of recovery and perioperative hemodynamics, respectively.. Randomized study.. Postoperative cardiac recovery unit, University Hospital.. Sixty patients with ischemic heart disease scheduled for elective coronary artery bypass grafting ± aortic valve replacement.. Randomized to either remifentanil or sufentanil anesthesia as basis opioid. Postoperative pain management consisted of morphine in both groups.. Cognitive functioning evaluated preoperatively and on the 1st, 4th, and 30th postoperative day using the cognitive test from the Palo Alto Veterans Affairs Hospital. Perioperative invasive hemodynamics and the quality of recovery was evaluated by means of invasive measurements and an intensive care unit discharge score.. No difference between opioids in POCD at any time. A negative correlation was found between preoperative cognitive function and POCD on the first postoperative day (r=-0.47; P=.0002). The fraction of patients with POCD on the first postoperative day was statistically greater in patients with more than 15minutes of Svo2 <60 (P=.037; χ(2) test). Among patients with postoperative ventilation time exceeding 300minutes, more patients had POCD on postoperative day 4 (P=.002).. We could not demonstrate differences in POCD between remifentanil and sufentanil based anaesthesia, but in general, the fraction of patients with POCD seemed smaller than previously reported. We found an association between POCD and both perioperative low Svo2 and postoperative ventilation time, underlining the importance of perioperative stable hemodynamics and possible fast-track protocols with short ventilation times to attenuate POCD.

Topics: Aged; Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Intravenous; Cardiac Surgical Procedures; Cognition; Cognition Disorders; Coronary Artery Bypass; Female; Humans; Male; Neuropsychological Tests; Pain Management; Pain, Postoperative; Piperidines; Remifentanil; Sufentanil

Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer's dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25-75 mg) and an open-label extension study (75 mg).. The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10-24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies.. A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (-2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, -0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, -0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, -1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters.. In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies.. ClinicalTrials.gov NCT01527916 , Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935 . Registered 29 August 2012 (open-label extension study).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cholinergic Agonists; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Piperidines; Quinuclidines; Thiadiazoles; Treatment Outcome

Electroconvulsive therapy (ECT) is among the most effective treatments of several life-threatening psychiatric disorder. Despite effective therapy, ECT-induced seizure could cause several adverse effects including cognitive disorders and memory impairment. Drugs such as thiopental, which have been prescribed for anesthesia required for ECT, are known as drugs with cognitive effects. This pilot randomized clinical trial tried to assess the feasibility of using a lower dose of thiopental in combination with remifentanil instead of a higher challenging dose of a single drug with cognitive side effects such as thiopental. We evaluated post-ECT cognitive impairment in patients who received remifentanil-thiopental compared with thiopental-placebo group.. One hundred twenty patients with psychiatric disorders between the ages of 18 and 60 years were enrolled. The patients were randomized into 2 groups who received either thiopental sodium (4 mg/kg) and remifentanil (1 μg/kg) or thiopental sodium (3 mg/kg, placebo). The psychiatric patients were examined using mini-mental state examination in terms of the cognitive deficits before ECT as well as 5 and 24 hours after ECT. Statistical analyses were done using Statistical Package for the Social Sciences version 16. Unpaired t test, χ2 test, and analysis of variance were used to determine the association of variables.. All the patients completed the trial. There were no reports of adverse effects. In terms of depth of anesthesia measured by bispectral index, no significant difference was observed. Regarding mini-mental state examination scores, the difference was not statistically significant.. Depth of anesthesia was similar between the groups.

Topics: Adolescent; Adult; Anesthesia; Anesthetics, Intravenous; Cognition Disorders; Consciousness Monitors; Double-Blind Method; Electroconvulsive Therapy; Female; Hemodynamics; Humans; Male; Mental Disorders; Middle Aged; Neuropsychological Tests; Pilot Projects; Piperidines; Remifentanil; Thiopental; Young Adult

The authors investigated the effect of remifentanil administration on resting electroencephalography functional connectivity and its relationship to cognitive function and analgesia in healthy volunteers.. Twenty-one healthy male adult subjects were enrolled in this placebo-controlled double-blind cross-over study. For each subject, 2.5 min of multichannel electroencephalography recording, a cognitive test of sustained attention (continuous reaction time), and experimental pain scores to bone-pressure and heat stimuli were collected before and after infusion of remifentanil or placebo. A coherence matrix was calculated from the electroencephalogram, and three graph-theoretical measures (characteristic path-length, mean clustering coefficient, and relative small-worldness) were extracted to characterize the overall cortical network properties.. Compared to placebo, most graph-theoretical measures were significantly altered by remifentanil at the alpha and low beta range (8 to 18 Hz; all P < 0.001). Taken together, these alterations were characterized by an increase in the characteristic path-length (alpha 17% and low beta range 24%) and corresponding decrements in mean clustering coefficient (low beta range -25%) and relative small-worldness (alpha -17% and low beta range -42%). Changes in characteristic path-lengths after remifentanil infusion were correlated to the continuous reaction time index (r = -0.57; P = 0.009), while no significant correlations between graph-theoretical measures and experimental pain tests were seen.. Remifentanil disrupts the functional connectivity network properties of the electroencephalogram. The findings give new insight into how opioids interfere with the normal brain functions and have the potential to be biomarkers for the sedative effects of opioids in different clinical settings.

Topics: Adult; Analgesia; Analgesics, Opioid; Attention; Brain; Cluster Analysis; Cognition; Cognition Disorders; Cross-Over Studies; Double-Blind Method; Electroencephalography; Humans; Male; Nerve Net; Neural Pathways; Pain; Pain Management; Piperidines; Reaction Time; Reference Values; Remifentanil; Young Adult

Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function.. A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated.. Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment.. Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Cholinesterase Inhibitors; Cognition Disorders; Combined Modality Therapy; Donepezil; Double-Blind Method; Female; Humans; Indans; Learning; Male; Memory; Middle Aged; Neoplasm Metastasis; Neuropsychological Tests; Piperidines; Treatment Outcome; Young Adult

The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to explore which tests and their measures are able to detect cognitive change after a single dose of donepezil in Alzheimer disease (AD) patients. The aim of this study was to establish the ability of CANTAB tests and their measures to detect cognitive change after a single 5-mg dose of donepezil in treatment-naïve AD patients.. We enrolled 62 treatment-naïve AD patients and 30 healthy controls in this prospective, randomized, rater-blinded study. AD patients were randomized to 2 groups: the AD+ group received donepezil after the first CANTAB testing and the AD- group remained treatment-naïve at second testing. The time period between repeated testing was 4 hours. Parallel versions of CRT, SOC, PAL, SWM, and PRM tests were used.. All groups did not differ according to age, education, gender, or depression (p>0.05). AD+ and AD- groups did not differ according to MMSE. SOC, PAL, PRM, and SWM tests distinguished AD from controls. Eight measures of PAL and PRM had a strong correlation with MMSE (r>0.7). Repeated-measures ANOVA with Bonferroni post-hoc test showed the difference of change in AD+ and AD- groups between first and second CANTAB testing in 7 PAL measures. AD+ and AD- groups differed in the second testing by 7 PAL measures. Four PAL measures differed in first and second testing within the AD+ group.. The CANTAB PAL test measures, able to detect cognitive change after a single dose of donepezil in AD patients, are: PAL mean trials to success, total errors (adjusted), total errors (6 shapes, adjusted), and total trials (adjusted).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognition; Cognition Disorders; Donepezil; Female; Humans; Indans; Learning; Male; Memory; Neuropsychological Tests; Pattern Recognition, Visual; Piperidines; Prospective Studies; Psychometrics; Severity of Illness Index; Time Factors; Treatment Outcome

Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16 weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78 weeks (18 months). Eighty DEP-CI outpatients (age 55 to 95 years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer's Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); and Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Antidepressive Agents; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Depressive Disorder; Donepezil; Double-Blind Method; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Piperidines; Research Design

Previous research has shown that resveratrol can increase cerebral blood flow (CBF) in the absence of improved cognitive performance in healthy, young human subjects during the performance of cognitively demanding tasks. This lack of cognitive effects may be due to low bioavailability and, in turn, reduced bioefficacy of resveratrol in vivo. Piperine can alter polyphenol pharmacokinetics, but previous studies have not investigated whether this affects the efficacy of the target compound. Therefore, the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol with regard to cognition and CBF. The present study utilised a randomised, double-blind, placebo-controlled, within-subjects design, where twenty-three adults were given placebo, trans-resveratrol (250 mg) and trans-resveratrol with 20 mg piperine on separate days at least a week apart. After a 40 min rest/absorption period, the participants performed a selection of cognitive tasks and CBF was assessed throughout the period, in the frontal cortex, using near-IR spectroscopy. The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography-MS analysis carried out following the administration of the same doses in a separate cohort (n 6). The results indicated that when co-supplemented, piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone. Cognitive function, mood and blood pressure were not affected. The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments, which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects, but not cognitive performance, and does this without altering bioavailability.

Topics: Adult; Alkaloids; Benzodioxoles; Cerebrovascular Circulation; Cognition; Cognition Disorders; Cohort Studies; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Female; Frontal Lobe; Humans; Intestinal Absorption; Male; Nootropic Agents; Pilot Projects; Piperidines; Polyunsaturated Alkamides; Resveratrol; Spectroscopy, Near-Infrared; Stilbenes; Task Performance and Analysis; Young Adult

In human beings, 5-HT6 receptors are almost exclusively expressed in the brain, particularly in areas relevant for cognition, such as the hippocampus and frontal cortex. We assessed the effect on cognitive performance of Lu AE58054 (idalopirdine), a selective 5-HT6 receptor antagonist, in donepezil-treated patients with moderate Alzheimer's disease.. For this randomised, double-blind, placebo-controlled phase 2 trial (LADDER), we recruited patients from 48 outpatient clinical sites in seven countries. Patients were 50 years or older, had moderate Alzheimer's disease (a mini-mental state examination score of 12-19), and had been stably treated with donepezil 10 mg per day for 3 or more months. Using a computer-generated sequence, we randomly assigned patients (1:1, stratified by site) to receive either idalopirdine 90 mg per day (30 mg thrice daily) or placebo. The primary endpoint was change from baseline in the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at week 24. We analysed all efficacy endpoints in the full-analysis set (modified intention-to-treat analysis). This trial is registered with ClinicalTrials.gov, number NCT01019421.. Between Dec 8, 2009, and Dec 23, 2011, we randomly allocated 278 patients to treatment: 133 to placebo and 145 to idalopirdine. 132 patients in the placebo group and 140 in the experimental group were included in the final analysis. At week 24, the change from baseline in ADAS-cog total score was +1·38 (SD 0·53) in the placebo group and -0·77 (0·55) in the idalopirdine group (treatment difference of -2·16 points, 95% CI -3·62 to -0·69; p=0·0040). 25 patients (seven taking placebo and 18 taking idalopirdine) discontinued treatment because of adverse events, the difference between groups being mainly due to asymptomatic transient increases in transaminase concentrations in some idalopirdine-treated patients. The most common adverse events (occurring in >3% of patients) were increased γ-glutamyltransferase (14 [10%] patients in the idalopirdine group vs two [2%] in the placebo group), diarrhoea (six [4%] vs nine [7%]), urinary tract infection (three [2%] vs nine [7%]), fall (three [2%] vs eight [6%]), increased alanine aminotransferase (nine [6%] vs none), and benign prostatic hyperplasia (two [5%] vs none). Serious adverse events were reported by 14 (10%) patients in the idalopirdine group and 13 (10%) patients in the placebo group. One death occurred in each treatment group, neither were regarded as being related to treatment.. Idalopirdine improved cognitive function in donepezil-treated patients with moderate Alzheimer's disease. Larger studies in a broader population of patients are ongoing to substantiate the effects reported here.. H Lundbeck A/S.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Benzylamines; Cognition Disorders; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Indoles; Male; Nootropic Agents; Piperidines; Receptors, Serotonin; Serotonin Antagonists; Treatment Outcome

The enigmatic etiology of neurodegenerative diseases poses a challenge for the development of novel and efficient drugs. The objective of the present study was to evaluate the efficacy of a polyherbal (test) formulation on cognitive functions, inflammatory markers and oxidative stress in healthy elderly as well as senile dementia of Alzheimer's type (SDAT) patients.. A randomized double-blind placebo- and active-controlled clinical trial was performed in healthy elderly subjects and SDAT patients with an age range of 60-75 years. The polyherbal test formulation along with a placebo was given to healthy elderly subjects while the SDAT patients received either the test formulation containing extracts of Bacopa monnieri (whole plant), Hippophae rhamnoides (leaves and fruits) and Dioscorea bulbifera (bulbils) at a dose of 500 mg or donepezil drug (Aricept) at a dose of 10 mg, twice daily, for a period of 12 months. After every three months, cognitive functions were assessed by determining the mini mental state examination (MMSE) score, digital symbol substitution (DSS; subtest of the Wechsler Adult Intelligence Scale-Revised), immediate and delayed word recall (digital memory apparatus-Medicaid systems, Chandigarh, India), attention span (Attention Span Apparatus-Medicaid systems, Chandigarh, India), functional activity questionnaire (FAQ) and depression (geriatric depression scale) scores. Further inflammatory markers and level of oxidative stress were analyzed using standard biochemical tests.. The trial was performed in 109 healthy subjects and 123 SDAT patients of whom 97 healthy subjects and 104 SDAT patients completed the study. Administration of the test formulation for a period of 12 months was effective in improving cognitive functions in the SDAT patients, when compared to the donepezil-treated group, as determined by the DSS (38.984 ± 3.016 vs 35.852 ± 4.906, P = 0.0001), word recall immediate (3.594 ± 1.003 vs 2.794 ± 0.593, P < 0.0001) and attention span (4.918 ± 1.239 vs 4.396 ± 0.913, P = 0.0208) scores. A significant improvement in the FAQ (11.873 ± 2.751 vs 9.801 ± 1.458, P < 0.0001) and depression (16.387 ± 2.116 vs 21.006 ± 2.778, P < 0.0001) scores was also observed, whereas no significant differences were observed in the MMSE and word recall delayed scores. The level of inflammation and oxidative stress was markedly reduced in the SDAT patients treated with the test formulation when compared to the donepezil-treated group indicating a likely mechanism of action of the test formulation (homocysteine 30.22 ± 3.87 vs 44.73 ± 7.11 nmol/L, P < 0.0001; C-reactive protein [CRP] 4.751 ± 1.149 vs 5.887 ± 1.049 mg/L, P < 0.0001; tumour necrosis factor alpha [TNF-α] 1139.45 ± 198.87 vs 1598.77 ± 298.52 pg/ml, P < 0.0001; superoxide dismutase [SOD] 1145.92 ± 228.75 vs 1296 ± 225.72 U/g Hb, P = 0.0013; glutathione peroxidase [GPx] 20.78 ± 3.14 vs 25.99 ± 4.11 U/g Hb, P < 0.0001; glutathione [GSH] 9.358 ± 2.139 vs 6.831 ± 1.139 U/g Hb, P < 0.0001; thiobarbituric acid reactive substances [TBARS] 131.62 ± 29.68 vs 176.40 ± 68.11 nmol/g Hb, P < 0.0001). Similarly, when healthy elderly subjects treated with the test formulation for 12 months were compared to the placebo group, a significant (P < 0.001) improvement in cognitive measures (MMSE, DSS, word recall delayed but not immediate, attention span, FAQ and depression scores) and a reduction in inflammation (reduction in homocysteine, CRP, IL-6 and TNF-α levels) and oxidative stress levels (reduction in SOD, GPx and TBARS and increase in GSH) was observed. This indicated a protective effect of the test formulation in managing cognitive decline associated with the ageing process.. The results of this study demonstrate the therapeutic potential of this novel polyherbal formulation for the management and treatment of SDAT.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Disease Management; Donepezil; Double-Blind Method; Drug Combinations; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Plant Components, Aerial; Plant Extracts; Plant Preparations

Topics: Aged; Anesthesia Recovery Period; Anesthetics, Intravenous; Cognition; Cognition Disorders; Consciousness Monitors; Female; Humans; Hypnotics and Sedatives; Intraoperative Neurophysiological Monitoring; Male; Middle Aged; Neuropsychological Tests; Piperidines; Pneumonectomy; Propofol; Recovery of Function; Remifentanil; Treatment Outcome

Use of cross-species neuropsychological paradigms such as visual-spatial paired associate learning (PAL) may allow for a better understanding of underlying neural substrates of memory. Such paradigms, which are often used to guide models of memory in animals, can then be carried forward into humans to provide a basis for evaluation of pharmacologic compounds designed to ameliorate learning and memory impairments in neurologic and psychiatric morbidities.. This double-blind, randomized, crossover trial investigated effects of donepezil, an acetylcholinesterase (AChE) inhibitor, in attenuating scopolamine-induced cognitive impairment using a novel, "process-based" computerized measure of visual-spatial PAL.. In healthy male volunteers, scopolamine (0.6 mg) induced a time-dependent reduction in visual-spatial PAL, with the greatest impairment (Cohen's d = 1.37) observed 2 h after dosing. Cotreatment with donepezil (10 mg) significantly ameliorated scopolamine-induced impairment at the 2-h time point (Cohen's d = 0.66). Process-based analyses revealed a significant impairment in both memory (Cohen's d = 1.37 to 0.50) and executive (Cohen's d = 1 .21 to 0.62) aspects of visual-spatial PAL performance following acute scopolamine challenge, and these reductions were ameliorated by donepezil.. Acute scopolamine challenge can produce large and robust deficits in visual-spatial PAL, which reflect impairments in both memory and executive processes. Coadministration of a single dose of donepezil can ameliorate these deficits. These results provide support for the use of a visual-spatial PAL test as a pharmacodynamic cognitive marker of central nervous system (CNS)-mediating compounds in humans.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Executive Function; Humans; Indans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Paired-Associate Learning; Piperidines; Scopolamine; Time Factors; Young Adult

To observe early intervention effects of Modified Shuyu Pill (MSP) on vascular cognitive impairment no dementia (VCIND).. Totally 100 patients VCIND were randomly assigned to the treatment group (43 cases) and the control group (33 cases). On the basis of the treatment targeting risk factors of blood vessels, patients in the treatment group were treated by MSP, while those in the control group were treated by donepezil hydrochloride. The therapeutic course was 16 weeks. The neuropsychological scales [mini-mental state examination (MMSE) and Montreal cognitive assessment (MOCA) score] and Chinese medicine dementia syndromes scales were observed before and after treatment.. The MMSE and MOCA score of the two groups increased when compared with the same group before treatment (P < 0.01). But there was no statistical difference in MMSE or MOCA score after treatment between the two groups (P > 0.05). The Chinese medicine dementia syndromes scales significantly decreased in the treatment group when compared with before treatment (P < 0.01). But there was no statistical difference in Chinese medicine dementia syndromes scales in the control group between before and after treatment (P > 0.05). There was statistical difference in Chinese medicine dementia syndromes scales after treatment between the two groups (P < 0.01).. MSP could effectively intervene the progress of VCIND.

Topics: Aged; Cognition Disorders; Donepezil; Drugs, Chinese Herbal; Early Medical Intervention; Female; Humans; Indans; Male; Middle Aged; Piperidines

Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration and synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments.

Topics: Analysis of Variance; Animals; Atrophy; Brain; Caloric Restriction; Case-Control Studies; Cognition Disorders; Cyclin-Dependent Kinase 5; Disease Models, Animal; Double-Blind Method; Excitatory Postsynaptic Potentials; Female; Green Fluorescent Proteins; Immunoprecipitation; In Vitro Techniques; Long-Term Potentiation; Male; Memory Disorders; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Nerve Tissue Proteins; Neurodegenerative Diseases; Phosphopyruvate Hydratase; Phosphotransferases; Piperidines; Silver Staining; Sirtuin 1; Synapses; Thiazoles; Tumor Suppressor Protein p53; Vitamin E

Treatment of Alzheimer's disease with acetylcholinesterase inhibitors can result in symptomatic benefits, but patients often show variable responses. The objective of this post hoc analysis was to investigate relationships between easily identifiable baseline characteristics/demographics and cognitive response in patients treated with either donepezil 23 mg/d or 10 mg/d and to identify factors potentially influencing response.. A post hoc analysis was conducted using data from a large, 24-week, randomized, double-blind, international study enrolling patients with moderate to severe Alzheimer's disease (baseline Mini-Mental State Examination [MMSE], 0-20) (NCT 00478205). Cognitive changes in subgroups of patients based on selected baseline and demographic characteristics were compared using the least squares mean changes in Severe Impairment Battery scores at Week 24. Univariate and multivariate analyses were also performed.. Donepezil 23 mg/d provided statistically significant incremental cognitive benefits over donepezil 10 mg/d irrespective of baseline functional severity, measured by scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living-severe version (P < 0.05). When patients were categorized by baseline cognitive severity (MMSE score), significant benefits of donepezil 23 mg/d over 10 mg/d were seen in both subgroups when based on MMSE scores of 0-9 versus 10-20 (P < 0.02 and P < 0.01, respectively), and in the more severe subgroup when based on MMSE scores of 0-16 versus 17-20 (P < 0.0001 and P > 0.05). Statistically significant incremental cognitive benefits of donepezil 23 mg/d over 10 mg/d were also observed regardless of age, gender, weight, or prestudy donepezil 10 mg/d treatment duration (P < 0.05). In the multivariate analysis, the only significant interaction was between treatment and baseline MMSE score.. The cognitive benefits of donepezil 23 mg/d over 10 mg/d were achieved regardless of the patient's age, gender, weight, duration of prior donepezil 10 mg/d, and functional severity. The influence of baseline cognitive severity on response seemed to be dependent on the level of impairment, with cognitive benefits of donepezil 23 mg/d over 10 mg/d most apparent in those patients at a more advanced stage of disease. These data may be useful in helping practicing physicians make informed decisions for their patients with advanced Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Piperidines; Severity of Illness Index; Treatment Outcome

The Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the SIB - the SIB-8 - which takes about 3 min to administer, may represent a more convenient tool for use in clinical practice. The current analyses further explored the SIB-8 scale with respect to its validity and sensitivity.. A post hoc analysis was performed using data from a 24-week trial of donepezil 23 mg/day and 10 mg/day in > 1400 patients with moderate to severe AD [baseline Mini-Mental State Examination (MMSE) score 0-20]. Treatment effects on cognition (patterns of score change) were assessed using the full SIB and SIB-8 in the total study population and subgroups based on concomitant memantine use and baseline MMSE. Internal consistency/agreement and correlations between the SIB and SIB-8 and other clinical end points were evaluated.. Assessment of score changes from baseline to week 24 with donepezil (23 or 10 mg/day) demonstrated comparable patterns of change when using the SIB-8 and the full SIB, despite inherent differences in the total score ranges for the two scales. Internal consistency/agreement between the full SIB and SIB-8 was good (Cronbach's alphas: 0.77-0.95). SIB-8 scores reliably correlated with SIB total scores (r = 0.859, baseline; r = 0.900, week 24; p < 0.0001), as well as MMSE scores (r = 0.7163, baseline; r = 0.7963, week 24; p < 0.0001). Scores on both SIB scales were moderately associated with functional measures at baseline and week 24.. In this post hoc analysis, similar treatment effects were measured by the full SIB and the SIB-8. Very good internal consistency/agreement and strong correlations between the SIB and the more rapid and convenient SIB-8 indicate that the SIB-8 may be a useful and efficient clinical proxy for the full SIB in evaluating treatment response in patients with advanced AD.

Topics: Activities of Daily Living; Alzheimer Disease; Analysis of Variance; Cognition Disorders; Donepezil; Double-Blind Method; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome

Drug development is a high-risk and high failure enterprise, and studies that provide an early read on the pharmacodynamic activity of novel compounds could save time and money, increasing the efficiency of the drug development process.. Preclinical and clinical experiments were designed to examine the utility of the scopolamine-induced cognitive impairment model in predicting pharmacodynamic signals of putatively procognitive compounds, utilizing the acetylcholinesterase inhibitor donepezil for illustration.. In normal healthy rats, scopolamine (0.3 mg/kg) significantly impaired performance on the two-platform water maze and on the T-maze. The deficits in water maze performance were reversed by donepezil at 0.5 and 1.0 mg/kg. There was a trend towards reversal of scopolamine-induced deficits in performance on the T-maze with 1.0 mg/kg donepezil. In normal healthy humans, scopolamine (0.3 and 0.5 mg) reliably impaired performance on the Cognitive Drug Research test battery composite scores (power of attention, continuity of attention, quality of working memory, quality of episodic secondary memory, and speed of memory) in a dose- and time-dependent manner. Donepezil (10 mg) significantly attenuated the scopolamine-induced impairment in cognition on power of attention, continuity of attention, quality of working memory, and speed of memory.. These findings suggest that reversal of scopolamine-induced cognitive impairment is a viable model for predicting pharmacodynamic signals of procognitive compounds in both animals and humans. The utility of the scopolamine-induced cognitive impairment model is discussed and illustrated at various decision points in drug development, with a focus on Go/No Go decisions.

Topics: Adult; Animals; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Design; Humans; Indans; Male; Maze Learning; Memory; Middle Aged; Muscarinic Antagonists; Nootropic Agents; Piperidines; Rats; Rats, Long-Evans; Scopolamine; Single-Blind Method; Species Specificity; Time Factors; Young Adult

To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia.. Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study.. In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects.. Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.

Topics: Adolescent; Adult; Analysis of Variance; Cannabinoid Receptor Antagonists; Cognition Disorders; Depression; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Pyrazoles; Rimonabant; Schizophrenia; Treatment Outcome; Young Adult

The purpose of this study was to evaluate the effects of blonanserin, a novel antipsychotic, on cognitive function in first-episode schizophrenia.. Twenty-four antipsychotic-naïve patients with first-episode schizophrenia participated in the study. Blonanserin was given in an open-label design for 8 weeks. The Brief Assessment of Cognition in Schizophrenia-Japanese language version (BACS-J) was administered as the primary outcome measure at baseline and 8 weeks. Clinical evaluation included the Positive and Negative Syndrome Scale (PANSS), the Schizophrenia Quality of Life Scale-Japanese language version (SQLS-J), and the Clinical Global Impression-Severity of Illness Scale (CGI-S). To exclude the possibility of retest effects on the BACS-J, 10 age-matched patients with chronic schizophrenia treated with blonanserin were tested at baseline and after an 8-week interval.. Twenty first-episode patients completed the study. Repeated measures analysis of covariance revealed a significant group-by-time interaction effect on the letter fluency task due to better performance in the first-episode group, but not in the control group. Main effect of time or group-by-time interaction effect on the Tower of London task was not significant; however, the first-episode group, but not the control group, showed substantial improvement with a moderate effect size. All items on the PANSS, SQLS-J, and CGI-S significantly improved after 8 weeks of treatment.. These results suggest that blonanserin improves some types of cognitive function associated with prefrontal cortical function.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Chronic Disease; Cognition Disorders; Female; Humans; Male; Piperazines; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Severity of Illness Index; Single-Blind Method; Treatment Outcome; Young Adult

Progressive neurodegeneration in Alzheimer's disease (AD) induces cognitive deterioration, and there is controversy regarding the optimal treatment strategy in early AD. Stimulation therapy, including physical exercise and cholinesterase inhibitors are both reported to postpone cognitive deterioration in separate studies. We aimed to study the effect of stimulation therapy and the additional effect of donepezil on cognitive function in early AD.. A two-by-two factorial trial comprising stimulation therapy for one year compared to standard care to which a randomized double-blinded placebo controlled trial with donepezil was added.. Nine rural municipalities in Northern Norway.. 187 participants 65 years and older with a recent diagnosis of mild or moderate AD were included in the study of which 146 completed a one-year follow-up.. In five municipalities the participants received stimulation therapy whereas participants in four received standard care. All participants were randomised double-blindly to donepezil or placebo and tested with three different cognitive tests four times during the one-year study period.. Changes in MMSE sum score.Secondary outcome: Changes in ADAS-Cog and Clock Drawing Test.. MMSE scores remained unchanged amongst AD participants receiving stimulation therapy and those receiving standard care. The results were consistent for ADAS-Cog and Clock Drawing Test. No time trend differences were found during one-year follow-up between groups receiving stimulation therapy versus standard care or between donepezil versus placebo.. In rural AD patients non-pharmacological and pharmacological therapy did not improve outcome compared with standard care but all groups retained cognitive function during one year follow-up. Other studies are needed to confirm these results.. ClinicalTrials.gov (Identifier: NCT00443014). EudraCT database (no 2004-002613-37).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Combined Modality Therapy; Comorbidity; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Norway; Physical Therapy Modalities; Piperidines; Prevalence; Treatment Outcome

To investigate whether the depth of total intravenous anesthesia affects postoperative cognitive dysfunction.. Ninety-six patients with facial spasm who were scheduled to receive microvascular decompression were randomly divided into 2 groups: deeper anesthesia (n = 50) and lighter anesthesia (n = 46). Exclusion criteria included: a history of neurologic or mental disease, serum creatinine in excess of 177 μmol/L, active liver disease, cardiac dysfunction, pulmonary dysfunction, endocrine disease, metabolic disease, a history of surgery, fewer than 6 years of school, inability to complete neuropsychologic testing, vision dysfunction, and auditory dysfunction. Propofol and sufentanil were used for anesthesia induction and propofol and remifentanil were used for the maintenance of anesthesia. A battery of 9 neuropsychologic was administered preoperatively and 5 days after surgery. A postoperative deficit was defined as a postop decrement to preop score greater than 1 standard deviation on any test. Patients who experienced 2 or more deficits were deemed to have early postoperative cognitive dysfunction.. Eighty patients completed both preoperative and postoperative neuropsychologic testing, of which 40 each were in the deeper and lighter anesthesia group. Postoperative early cognitive dysfunction occurred in 4 patients (10%) in the deeper anesthesia group and in 11 patients (27.5%) in the lighter anesthesia group. The incidence of the postoperative cognitive dysfunction was significantly reduced in the deeper anesthesia group compared with the lighter anesthesia group (P < 0.05, χ).. Deeper total intravenous anesthesia can decrease the incidence of cognitive dysfunction in the early postoperative period.

Topics: Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Cognition Disorders; Consciousness Monitors; Decompression, Surgical; Female; Hemifacial Spasm; Humans; Intraoperative Awareness; Male; Middle Aged; Neuropsychological Tests; Patient Dropouts; Piperidines; Postoperative Complications; Propofol; Remifentanil

AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12-26). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 21-26). Mean age was 74 (range 58-85) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 25-26) indicated improvement versus placebo for AZD3480 20 mg (-1.4, 95% CI: -3.0; 0.2) and donepezil (-1.0, 95% CI: -2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria: since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating α4β2 receptors with NNRs in AD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Neuroprotective Agents; Neuropsychological Tests; Piperidines; Pyridines; Time Factors; Treatment Outcome

Down syndrome (DS) patients share certain neuropathological features with Alzheimer disease patients. A randomized, double-blind, placebo-controlled study was performed to investigate the efficacy and safety of donepezil, an Alzheimer disease drug, for DS patients.. Twenty-one DS patients with severe cognitive impairment were assigned to take donepezil (3 mg daily) or a placebo for 24 weeks, and evaluated for activities in daily lives by concisely modified International Classification of Functioning, Disability and Health (ICF) scaling system.. ICF scores significantly increased without any adverse effects in the donepezil group in comparison to those in the placebo control. Among the individual functions tested, there was a dramatic improvement in the global mental functions and in specific mental functions.. Donepezil may effectively and safely improve overall functioning of DS patients with severe cognitive impairment.

Topics: Activities of Daily Living; Adult; Cognition Disorders; Donepezil; Double-Blind Method; Down Syndrome; Female; Humans; Indans; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Quality of Life; Treatment Outcome

The Positive and Negative Syndrome Scale (PANSS) total score is widely used to assess antipsychotic efficacy, however schizophrenia is a multi-dimensional disorder. We conducted a 5-factor analysis for evaluating the efficacy of iloperidone vs. placebo across these different domains in the treatment of schizophrenia.. The 5-factor model was determined from pooled data from 7 clinical trials (4 placebo- and active-controlled and 3 non-inferiority active-comparator trials of iloperidone) in schizophrenia (N=3580).Five factors were derived (excitement/hostility [P4,P7,G8,G14], depression/anxiety [G1,G2,G3,G4,G6], cognition [P2,N5,N7,G5,G10,G11,G12,G13,G15], positive [P1,P3,P5,P6,G9], and negative [N1,N2,N3,N4,N6,G7,G16]) from a factor analysis on the covariance matrix of 30 baseline PANSS items using a varimax rotation; factors retained had eigenvalues of ≥ 0.5. These newly derived 5 factors differ only slightly from other 5-factor analyses published by others using different datasets. The analysis of covariance model was then applied to assess these efficacy outcomes from the 4-6 week double-blind placebo and active controlled clinical trials of iloperidone.. Based on the placebo-controlled trials, iloperidone improvements from baseline (least squared mean change ± standard error) were as follows: excitement/hostility, 0.4 ± 0.21 for 10-16 mg, 0.6 ± 0.43 for 20-24 mg vs. -1.0 ± 0.23 for placebo; P<0.001 for both iloperidone doses vs. placebo; depression/anxiety, 1.9 ± 0.21 for 10-16 mg, 1.9 ± 0.41 for 20-24 mg vs. 1.1 ± 0.22 for placebo; P<0.05 for 10-16 mg dose vs. placebo; cognition, 2.8 ± 0.35 for 10-16 mg, 3.9 ± 0.69 for 20-24 mg vs. 1.6 ± 0.38 for placebo; P<0.05 for both iloperidone doses vs. placebo; positive, 3.7 ± 0.26 for 10-16 mg, 4.1 ± 0.53 for 20-24 mg vs. 2.7 ± 0.29 for placebo; P<0.05 for both iloperidone doses vs. placebo; and negative, 2.2 ± 0.29 for 10-16 mg, 2.5 ± 0.58 for 20-24 mg vs. 1.3 ± 0.32 for placebo; P<0.05 for 10-16 mg vs. placebo. Active controls validated iloperidone efficacy.. Iloperidone demonstrated positive treatment effects on these newly derived PANSS factors. The 10-16 mg and 20-24 mg dose groups had similar efficacy on the PANSS factors, with the exception of the depression/anxiety and negative factors, on which the 10-16 mg dose group showed statistical separation from placebo and the 20-24 mg dose group did not. At 6 weeks, the lack of separation from placebo for the higher dose group may have been due to the much smaller sample size in that group.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Factor Analysis, Statistical; Female; Follow-Up Studies; Humans; Isoxazoles; Male; Middle Aged; Mood Disorders; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome; Young Adult

Donepezil has been proven effective in the treatment of Alzheimer's disease and vascular dementia. However, its effects on the cognitive neural network have not been fully investigated. The purpose of this study was to evaluate the effect of donepezil on reorganisation of the cognitive neural network in patients with post-stroke cognitive impairment using functional MRI (fMRI). Fourteen patients with stroke in the right hemisphere were enrolled. Participants were randomly assigned to the experimental or the control group. Donepezil (5 mg) or placebo was administered daily for four weeks. Cognitive function assessment was performed before and immediately after treatment, and repeated one month after cessation of treatment. fMRI was performed before and after treatment. Ten out of 14 patients (six in the experimental group, four in the control group) successfully completed all experimental processes. The experimental group showed significant improvements in the Mini-Mental Status Examination during the post-treatment evaluation and one-month follow-up compared to the pre-treatment evaluation (p < .05). No improvement was observed in the control group. In the experimental group fMRI showed increased activation in both prefrontal areas, both inferior frontal lobes, and in the left inferior parietal lobe. Increased recruitment of the parieto-frontal networks in the selected patients was considered to be a neural correlate of cognitive improvement induced by donepezil.

Topics: Adult; Aged; Brain Mapping; Cognition Disorders; Donepezil; Female; Functional Laterality; Humans; Indans; Male; Middle Aged; Neural Pathways; Neuropsychological Tests; Nootropic Agents; Pilot Projects; Piperidines; Stroke

Topics: Adolescent; Adult; Aged; Cognition Disorders; Disability Evaluation; Donepezil; Double-Blind Method; Executive Function; Female; Humans; Indans; Male; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; Nootropic Agents; Piperidines; Retrospective Studies; Treatment Outcome; Verbal Learning; Young Adult

We investigated whether the early postoperative cognitive dysfunction (POCD) was affected by different perioperative analgesia methods using intravenous remifentanil or epidural ropivacaine in the elderly undergoing major upper abdominal surgery.. Twenty elderly patients (aged over 60 years) undergoing elective surgery for distal or pylorus-preserving gastrectomy under general anesthesia were enrolled in this study. The patients were randomly allocated to two groups : Group LV (n = 10) of intravenous remifentanil, and Group EPI (n = 10) of epidural ropivacaine. The dose of both analgesic agents was controlled to keep stable hemodynamics. We recorded postoperative outcome and complications, and assessed cognitive status at the preoperative period and on the 7th postoperative day using 6 cognitive assessment tests.. POCD occurred in one case (10%) in group IV and two cases (20%) in group EPI (P = 0.50). VAS score, the days of hospital stay and the frequency of additional analgesics were similar between the groups.. Perioperative analgesia using intravenous remifentanil and epidural ropivacaine showed no significant difference in the incidence of early POCD after upper abdominal surgery in elderly patients.

Topics: Aged; Amides; Analgesia; Analgesia, Epidural; Anesthesia, General; Cognition Disorders; Female; Gastrectomy; Humans; Incidence; Infusions, Intravenous; Male; Middle Aged; Perioperative Care; Piperidines; Postoperative Complications; Pylorus; Remifentanil; Ropivacaine

The progression of cognitive deterioration in patients with Alzheimer's disease (AD) is considerably variable. The ability to predict the progression rate is important for clinicians to treat and manage patients with AD. We examined the possible relationship between the rate of cognitive deterioration and regional cerebral blood flow (rCBF) patterns in patients with AD.. We followed 48 patients with AD for an average of 37 months. They were subsequently divided into the rapidly progressing group (n=24) and slowly progressing group (n=24) based on an annual Mini-Mental State Examination (MMSE) score change. Initial and follow-up rCBF were assessed using single photon emission CT (SPECT) and the SPECT data were analyzed by 3D-stereotactic surface projections.. At initial evaluation, the rapidly progressing group had greater rCBF deficits mainly in the parietotemporal and frontal regions, and left posterior cingulate than did the slowly progressing group. When compared with initial SPECT, follow-up SPECT showed a significant rCBF reduction in widespread regions, including parietotemporal and frontal lobes, of the rapidly progressing group, while showed in the scattered and small regions of hemispheres of the slowly progressing group.. Our longitudinal SPECT study suggests a significant association between rCBF deficits in the parietotemporal, posterior cingulate, and frontal regions and subsequent rapid cognitive and rCBF deterioration.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Mapping; Cerebral Arteries; Cerebral Cortex; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disability Evaluation; Disease Progression; Donepezil; Female; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Piperidines; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Severity of Illness Index; Time Factors; Tomography, Emission-Computed, Single-Photon

Following a 48-week, double-blind, randomized, placebo-controlled trial of donepezil in 821 patients with amnestic mild cognitive impairment (aMCI), safety and tolerability of donepezil (10 mg) were further evaluated in a 28-week extension study. Of 499 participants who completed the double-blind phase, 145 enrolled in the open-label study. Adverse events (AEs) were recorded throughout. Overall, 57.4% of participants in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE, with the most frequent treatment-emergent AEs being diarrhea, muscle spasms, insomnia, and nausea. Most were mild to moderate in severity and were more common in the first several weeks after treatment initiation. More participants in the placebo/donepezil group (22.1%) discontinued donepezil due to an AE compared with the donepezil/donepezil group (10.3%). These findings support the safety of donepezil in patients with aMCI. When compared with other studies, however, the data suggest that patients with Alzheimer's tolerate donepezil better than patients with MCI.

Topics: Adult; Aged; Aged, 80 and over; Amnesia; Cholinesterase Inhibitors; Cognition Disorders; Diarrhea; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Nausea; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Spasm; Time Factors; Treatment Outcome

To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment. Relationships to global and functional measures were explored. The difference between donepezil- and placebo-treated patients in least squares (LS) mean change in SIB total scores from baseline to week 24 was 6.22 (p < 0.0001, Cohen's d, 0.53). Treatment-placebo differences were statistically significant for each baseline severity stratum, being greatest for the MMSE 6-9 stratum (LS mean difference, 7.60; p < 0.0001, Cohen's d, 0.66). Treatment-placebo differences in LS mean change in SIB domain scores significantly favored donepezil for seven of nine domains (range, p = 0.0056 to p < 0.0001; Cohen's d, 0.17-0.48). Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5-10 mg/day) in children (aged 10-17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between-group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated.

Topics: Adolescent; Behavior; Caregivers; Child; Cholinesterase Inhibitors; Cognition Disorders; Diarrhea; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Down Syndrome; Drug Tolerance; Female; Humans; Indans; Learning; Male; Neuropsychological Tests; Piperidines; Severity of Illness Index; Vomiting

Cholinesterase-inhibitor therapy is approved for treatment of Alzheimer disease; however, application in patients with mild cognitive impairment (MCI) is still under active investigation. The purpose of this study was to determine the effect of such therapy on the neural substrates underlying memory processing in subjects with MCI by using functional MR imaging (fMRI).. Thirteen subjects with MCI (mean age, 68 +/- 6.9 years) enrolled in a multicenter double-blind placebo-controlled trial testing the clinical efficacy of the cholinesterase-inhibitor, donepezil, were studied with fMRI at baseline and following 12 or 24 weeks of therapy (single-site pilot study). The cognitive paradigm was delayed-response visual memory for novel faces. Within-group 1-sample t tests were performed on the donepezil and placebo groups at baseline and at follow-up. A repeated-measures analysis of variance design was used to look for a Treatment Group x Time interaction showing a significant donepezil- but not placebo-related change in blood oxygen level-dependent response during the course of the study.. At baseline, both groups showed multiple areas of activation, including the bilateral dorsolateral prefrontal cortex, fusiform gyrus, and anterior cingulate cortex. On follow-up, the placebo group demonstrated a decreased extent of dorsolateral prefrontal activation, whereas the donepezil group demonstrated an increased extent of activation in the ventrolateral prefrontal cortex. Interaction demonstrated significant donepezil- but not placebo-related change in the left inferior frontal gyrus.. Despite the limitations inherent to a pilot study of a small sample, our results point to specific cortical substrates underlying the actions of donepezil, which can be tested in future studies.

Topics: Aged; Cerebral Cortex; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Nootropic Agents; Pilot Projects; Piperidines; Placebos; Severity of Illness Index

Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms.. In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function.. The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%).. Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Double-Blind Method; Endpoint Determination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Outcome Assessment, Health Care; Patient Compliance; Piperidines; Severity of Illness Index; Treatment Outcome

Change in cognitive function in response to a pharmacologic challenge can be observed with greater sensitivity by employing cognitive tests with optimal psychometric properties and a statistical approach that more accurately accounts for individual variability in performance. To demonstrate this approach we examined the cognitive effects of a single acute dose administration of an acetylcholinesterase inhibitor, donepezil, in healthy older adults and in older adults with mild Alzheimer's disease (AD).. Placebo-controlled crossover study with three separate testing days: baseline, placebo, and donepezil, with assessments at baseline, and 1-, 2-, 3-, 6-, and 8-hrs post-dosing on each day.. Early phase I clinical trial.. 15 healthy older adults; 14 older adults with mild Alzheimer's disease.. Single acute dose of 5mg donepezil.. Performance on the Groton Maze Learning Test (GMLT), a computerized neuropsychological measure of spatial working memory and error monitoring.. A single acute dose of donepezil improved GMLT performance in healthy older adults (effect size: 0.83 at 6 hrs post-dosing) and older adults with mild AD (effect size: 0.58 at 3 hrs post-dosing).. The GMLT detected cognitive improvement following a single, acute dose administration of donepezil in healthy older adults and older adults with mild AD. The choice of cognitive tests designed for repeated administration, as well as an analytic approach that emphasizes individual-level change in cognitive function, provides a sensitive approach to detecting central nervous system drug penetration and activity of cognitive-enhancing agents.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Humans; Indans; Male; Maze Learning; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Piperidines; Psychometrics; Reproducibility of Results; Research Design; Sensitivity and Specificity

Despite the beneficial effects of atypical antipsychotics on cognition, many schizophrenic patients continue to suffer from cognitive impairment. Postmortem findings suggest that altered cholinergic activity is involved in cognitive impairment in schizophrenia.. This study investigated whether adjunctive donepezil added to atypical antipsychotics can improve cognition in schizophrenic patients.. We conducted an open-label trial of donepezil, at doses of up to 10 mg/day for 12 weeks, added to ongoing atypical antipsychotics in 28 stable schizophrenic patients. At baseline and 12 weeks, the patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Schizophrenia Cognition Rating Scale (SCoRS), and Computerized Neurocognitive Function Test (CNT).. Donepezil treatment resulted in significant improvements in attention, memory, psychomotor speed, and mental set-shifting ability.. Adjunctive treatment with donepezil improves cognition in patients with schizophrenia who are stabilized on atypical antipsychotics. Further studies controlling for smoking, age, and severity of cognitive impairment of the participants are needed.

Topics: Adult; Antipsychotic Agents; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship.. The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD.. Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score > or =10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants.. Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Brain; Cholinesterase Inhibitors; Cognition Disorders; Depressive Disorder; Disease Progression; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Placebos; Severity of Illness Index; Time Factors; Tocopherols; Treatment Outcome

Older adults with cognitive problems have a higher risk of falls, at least twice that of cognitively normal older adults. The consequences of falls in this population are very serious: fallers with cognitive problems suffer more injuries due to falls and are approximately five times more likely to be admitted to institutional care. Although the mechanisms of increased fall risk in cognitively impaired people are not completely understood, it is known that impaired cognitive abilities can reduce attentional resource allocation while walking. Since cognitive enhancers, such as cholinesterase inhibitors, improve attention and executive function, we hypothesise that cognitive enhancers may reduce fall risk in elderly people in the early stages of cognitive decline by improving their gait and balance performance due to an enhancement in attention and executive function.. Double blinded randomized controlled trial with 6 months follow-up in 140 older individuals with Mild Cognitive Impairment (MCI). Participants will be randomized to the intervention group, receiving donepezil, and to the control group, receiving placebo. A block randomization by four and stratification based on fall history will be performed. Primary outcomes are improvements in gait velocity and reduction in gait variability. Secondary outcomes are changes in the balance confidence, balance sway, attention, executive function, and number of falls.. By characterizing and understanding the effects of cognitive enhancers on fall risk in older adults with cognitive impairments, we will be able to pave the way for a new approach to fall prevention in this population. This RCT study will provide, for the first time, information regarding the effect of a medication designed to augment cognitive functioning have on the risk of falls in older adults with Mild Cognitive Impairment. We expect a significant reduction in the risk of falls in this vulnerable population as a function of the reduced gait variability achieved by treatment with cognitive enhancers. This study may contribute to a new approach to prevent and treat fall risk in seniors in early stages of dementia.. The protocol for this study is registered with the Clinical Trials Registry, identifier number: NCT00934531 http://www.clinicaltrials.gov.

Topics: Accidental Falls; Aged; Aged, 80 and over; Cholinesterase Inhibitors; Clinical Protocols; Cognition Disorders; Community-Based Participatory Research; Donepezil; Double-Blind Method; Female; Gait; Humans; Indans; Male; Patient Selection; Piperidines; Treatment Outcome

Topics: Aged; Alzheimer Disease; Art; Cognition Disorders; Combined Modality Therapy; Donepezil; Humans; Indans; Nootropic Agents; Nursing Homes; Occupational Therapy; Piperidines; Quality of Life; Social Support; Treatment Outcome

Impairments in cognition and motivation are common after stroke and predict poor functional recovery. Pharmacological agents that enhance cognition and/or diminish apathy may, when combined with traditional rehabilitative efforts, improve functional recovery. We investigated the feasibility of using acetylcholinesterase inhibitors in older patients with acute post-stroke cognitive impairment and examined their effects on functional recovery.. This 12-week open-label study prospectively treated ischemic stroke survivors aged > or =60 years who were undergoing inpatient rehabilitation and who had cognitive impairment in one or more domains (memory, attention or executive function). Participants received galantamine (maximum dose 24 mg/day) or donepezil (maximum dose 10 mg/day). Physical function was assessed using the Functional Independence Measure-motor subscale (FIM-motor); participants' functional gains were compared to those of a matched historical comparator group. Changes in cognition and apathy were also assessed. Since donepezil and galantamine have different pharmacologic profiles, they were examined separately.. Forty participants started study medication; 14 participants terminated prematurely. Donepezil-treated participants experienced a 14-point greater improvement in the FIM-motor score compared to either galantamine-treated participants or the historical comparator group (repeated measures mixed model, group x time interaction p < 0.0001). Change in apathy, but not in cognition, was also associated with change in the FIM-motor score.. In this open-label study, participants receiving donepezil had better functional recovery than participants receiving galantamine or the historical comparators. This improvement may reflect efficacy at the starting dose for donepezil but not galantamine. A randomized trial is in progress.

Topics: Aged; Attention; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Feasibility Studies; Female; Galantamine; Humans; Indans; Male; Middle Aged; Motivation; Motor Activity; Nootropic Agents; Pilot Projects; Piperidines; Prospective Studies; Recovery of Function; Stroke; Treatment Outcome

To build and analyze regression models predicting (1) the long-term cognitive outcome in donepezil-treated patients with Alzheimer's disease, and (2) the short-term (6 months) cognitive impact of treatment depending on cognitive severity at baseline.. The Swedish Alzheimer Treatment Study (SATS) is an open-label, non-randomized, 3-year, multicentre study in a routine clinical setting. A total of 435 patients, mostly in the mild and moderate stages of Alzheimer's disease, received the cholinesterase inhibitor donepezil. They were assessed with the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at baseline and every 6 months for a total period of 3 years. Regression models were fitted from the actual scores at different intervals for the prediction of the cognitive outcome.. The ADAS-cog and MMSE scores during the 3-year treatment period could be predicted with a high degree of explanation using regression models (p < 0.001). Moreover, there was a significant relation between the mean cognitive change after 6 months of treatment and the baseline scores on MMSE (p < 0.01) and ADAS-cog (p < 0.001), respectively.. Statistical models can be used to predict cognitive outcome in donepezil-treated cohorts of AD patients. These models can be clinically valuable, for example when assessing the efficacy of new therapies when added to cholinesterase inhibitor treatment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Donepezil; Female; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Models, Statistical; Nootropic Agents; Patient Dropouts; Piperidines; Predictive Value of Tests; Psychiatric Status Rating Scales; Regression Analysis; Severity of Illness Index

White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer's disease (AD) is less clear.. Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD. WMH from multiple brain regions were scored on MR images obtained at entry into the trial from a subset of 152 study participants using a standardized visual rating scale. Cox proportional hazards models adjusting for age, education and treatment arm were used to investigate the role of WMH on time to progression.. 55 of the 152 (36.2 %) aMCI subjects progressed to AD. Only periventricular hyperintensities (PVH) were related to an increased risk of AD within three years (HR = 1.59, 95 % CI = 1.24 - 2.05, p-value < 0.001). Correcting for medial temporal lobe atrophy or the presence of lacunes did not change statistical significance.. PVH are associated with an increased risk of progression from aMCI to AD. This suggests that PVH, an MRI finding thought to represent cerebrovascular damage, contributes to AD onset in vulnerable individuals independent of Alzheimer pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Antioxidants; Atrophy; Brain; Cerebral Ventricles; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Piperidines; Prospective Studies; Temporal Lobe; Time Factors; Treatment Outcome; Vitamin E

The vitamin E and donepezil trial for the treatment of amnestic mild cognitive impairment (MCI) was conducted at 69 centers in North America; 24 centers participated in an MRI sub study. The objective of this study was to evaluate the effect of treatment on MRI atrophy rates; and validate rate measures from serial MRI as indicators of disease progression in multi center therapeutic trials for MCI. Annual percent change (APC) from baseline to follow-up was measured for hippocampus, entorhinal cortex, whole brain, and ventricle in the 131 subjects who remained in the treatment study and completed technically satisfactory baseline and follow-up scans. Although a non-significant trend toward slowing of hippocampal atrophy rates was seen in APOE is an element of 4 carriers treated with donepezil; no treatment effect was confirmed for any MRI measure in either treatment group. For each of the four brain atrophy rate measures, APCs were greater in subjects who converted to AD than non-converters, and were greater in APOE is an element of 4 carriers than non-carriers. MRI APCs and changes in cognitive test performance were uniformly correlated in the expected direction (all p<0.000). Results of this study support the feasibility of using MRI as an outcome measure of disease progression in multi center therapeutic trials for MCI.

Topics: Aged; Aged, 80 and over; Antioxidants; Atrophy; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Hippocampus; Humans; Incidence; Indans; Longitudinal Studies; Male; Middle Aged; Piperidines; Treatment Outcome; United States; Vitamin E

AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was -0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Dioxoles; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Psychomotor Performance; Risperidone; Sample Size; Schizophrenia; Schizophrenic Psychology

This paper reviews the key lessons learned from the first published short-term, placebo-controlled trial of a cholinesterase inhibitor for treatment of mild cognitive impairment (MCI).. The study was a 24-week placebo-controlled trial designed to evaluate the efficacy and safety of donepezil HCl (donepezil) in the treatment of cognitive impairment in subjects with MCI. Primary outcome measures were the NYU Paragraphs Test and the ADCS Clinicians Global-Impression of Change in the intent-to-treat last-observation-carried-forward group.. There was no benefit of donepezil treatment on primary outcome measures (NYU Paragraphs and ADCS CGI-C) in the ITT-LOCF group but positive findings were seen on NYU Paragraphs in the fully evaluable group and in certain secondary outcome measures across both groups.. The results highlight the need for the use of primary cognitive and functional measures that are reliable and sensitive to change in patients with MCI. Measures of episodic memory, psychomotor speed and complex attention were most sensitive in this study. Functional rating scales are needed that measure change in individual subjects' key areas of functional deficit, which typically involve executive aspects of instrumental ADLs. Tolerability can be increased by use of flexible dosing and efficacy is likely to be enhanced by increasing the length of the trial from six to 12 months and by enriching the sample with subjects more likely to decline during the trial.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Donepezil; History, 20th Century; Humans; Indans; Memory Disorders; Neuropsychological Tests; Outcome Assessment, Health Care; Piperidines; Placebos; Psychiatric Status Rating Scales; Psychomotor Performance; Randomized Controlled Trials as Topic; Research Design; Severity of Illness Index; Treatment Outcome; United States

Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18-55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n=121; placebo, n=124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p=0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p=0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil- and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebo-treated patients, and is a serious consideration in future clinical trial study desig

Topics: Adult; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Placebo Effect; Practice, Psychological; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Time Factors

To assess combined antidepressant and cognitive enhancer treatment in elderly patients presenting with depression plus cognitive impairment.. Twenty-three elderly (>50 years old) depressed, cognitively impaired (DEP-CI) patients participated in a pilot study. We evaluated whether, after 8 weeks of open antidepressant treatment, donepezil HCl (Aricept) would afford added cognitive benefit compared to placebo in a randomized 12-week trial. A subsample continued in an 8-month extension phase of open treatment with donepezil. Neuropsychological testing (NPT) was performed and antidepressant response monitored at baseline and the 8, 20, and 52-week time points.. At 8-weeks, the antidepressant response rate was 61% (14/23). Improvement in SRT immediate recall (SRT-IR; e.g. episodic verbal memory) was observed in responders compared to non-responders. During the 12-week, placebo-controlled, donepezil add-on trial, patients on donepezil showed further improvement in SRT-IR versus patients on placebo. In the open extension phase, patients who continued open donepezil treatment (n = 6) maintained improvement in memory and tended to show an advantage over patients who never received donepezil and were evaluated at the 52-week time point (n = 6). There were no observed significant donepezil effects on non-memory cognitive domains.. These preliminary findings suggest that addition of a cholinesterase inhibitor (AChEI) following antidepressant medication treatment in elderly Dep-CI patients may improve cognition, and support the need for a confirmatory, larger randomized placebo-controlled trial.

Topics: Aged; Antidepressive Agents; Cholinesterase Inhibitors; Cognition Disorders; Depressive Disorder; Donepezil; Epidemiologic Methods; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Sertraline; Treatment Outcome

To determine whether donepezil is effective in enhancing cognitive functioning and instrumental activities of daily living (IADLs) in older adults with bipolar disorder.. Twelve elderly patients with bipolar I or II disorder, with evidence of mild cognitive decrements, were administered donepezil 5-10 mg daily for 3 months. Participants had cognitive and functional evaluation pre-, on-, and 3-months post donepezil administration.. Three subjects dropped out of the study. In the remaining nine subjects, no significant effects were observed in cognitive and functional measures. Seven of the nine participants asked to resume the medication after completion of the study because of the perceived beneficial effects.. In this small pilot study of older adults with bipolar disorder, acute treatment with donepezil was not associated with improvements in cognitive and IADL functioning. Given limitations of the study design, placebo effects could not be ruled out in the subjects who asked to resume donepezil.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Bipolar Disorder; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Pilot Projects; Piperidines; Prospective Studies; Psychiatric Status Rating Scales

In the UK it is recommended that acetylcholinesterase inhibitors be restricted to patients with moderate Alzheimer's disease, and progress monitored within specialist clinics.. To describe a cohort of patients with Alzheimer's disease from a whole city population treated with donepezil, and to analyse outcomes over 4 years.. Historical cohort design: 88 patients recruited 1997-1998, assessed at baseline with 4-year follow-up, using an agreed protocol and validated measures: survival, retention in treatment, cognition, non-cognitive symptoms, weight change, carer stress.. 64.7% remained on treatment beyond 6 months, 57.9% beyond 1 year and 12.5% beyond 4 years. 56% remained alive at 4 years - almost twice the number predicted. Mean MMSE score amongst patients in treatment did not deteriorate over 4 years. Survival, retention in treatment, maintenance/improvement of cognition was greater with high baseline MMSE. Non-cognitive symptoms, carer stress and weight change remained low throughout.. A minority of people with dementia from the population (88 of potential 2,000 at outset, 11 by 4 years) received treatment. Benefits for individuals were confirmed, especially for those with mild impairment. Expenditure on medication was modest in a population context. These findings question recent guidance from the National Institute for Clinical Excellence, which would restrict therapy to patients with moderate cognitive impairment.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Severity of Illness Index

Cholinergic deficits might contribute to vascular cognitive impairment. Trials of cholinesterase inhibitors in patients with vascular dementia are difficult because of heterogeneous disease mechanisms and overlap between vascular and Alzheimer's disease (AD) pathology in the age-group recruited. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a genetic form of subcortical ischaemic vascular dementia. It represents a homogeneous disease process, and because of CADASIL's early onset, comorbid AD pathology is rare. We did a multicentre, 18-week, placebo-controlled, double-blind, randomised parallel-group trial to determine whether the cholinesterase inhibitor donepezil improves cognition in patients with CADASIL.. 168 patients with CADASIL (mean age 54.8 years) were assigned to 10 mg donepezil per day (n=86) or placebo (n=82) by a computer-generated randomisation protocol. Inclusion criteria included a mini-mental state examination (MMSE) score of 10-27 or a trail making test (TMT) B time score at least 1.5 SD below the mean, after adjustment for age and education. The primary endpoint was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Secondary endpoints included scores on the ADAS-cog, MMSE, TMT A time and B time, Stroop, executive interview-25 (EXIT25), CLOX, disability assessment for dementia, and sum of boxes of the clinical dementia rating scale. Analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00103948.. 161 patients were analysed. There was no significant difference between donepezil (n=84) and placebo (n=77) in the primary endpoint. The least-squares mean change from baseline score was -0.81 (SE 0.59) in the placebo group and -0.85 (SE 0.57) in the donepezil group (p=0.956). There was a significant treatment effect favouring donepezil on the following secondary outcomes: TMT B time (p=0.023), TMT A time (p=0.015), and EXIT25 (p=0.022). Ten donepezil-treated patients discontinued treatment due to adverse events compared to seven placebo-treated patients.. Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. Our findings may have implications for future trial design in subcortical vascular cognitive impairment.

Topics: Adult; Aged; CADASIL; Cognition Disorders; Confidence Intervals; Donepezil; Double-Blind Method; Female; Humans; Indans; International Cooperation; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Problem Solving

To study the effects of acetylcholinesterase inhibitors (AChEIs) in the management of cognitive impairments in patients with schizophrenia, we investigated the effects of 12 weeks of adjunctive therapy with donepezil on their cognitive impairments. Twenty-four subjects stabilized on haloperidol treatment (5-30 mg/day) for a minimum of 3 months were entered into a double-blind, placebo-controlled trial of donepezil as an adjunctive treatment. Subjects were randomly assigned under double-blind conditions to receive either 5 mg/day donepezil (N = 12) or pLacebo (N = 12) for 12 weeks. The subjects were evaluated at baseline, and after 4, 8, and 12 weeks using the Korean version of Mini Mental State Examination (K-MMSE), Brief Psychiatric Rating Scale (BPRS), and standard neuropsychological assessment. The K-MMSE scores improved significantly (p < 0.05) but the BPRS scores did not improve significantly in patients given donepezil; subjects showed slight improvement in several cognitive measures. At the end of the study, the difference in the mean K-MMSE scores between the donepezil and placebo groups approached statistical significance (p = 0.056). Of the several domains of cognitive functions assessed, verbal recognition and visual recall memory improved significantly (p < 0.05). But donepezil did not affect scores in the executive function tests. Our findings support a potential positive effect of AChEIs in the management of cognitive impairments in patients with chronic schizophrenia. Further studies with large subjects are needed to confirm our findings.

Topics: Adult; Antipsychotic Agents; Cholinesterase Inhibitors; Chronic Disease; Cognition Disorders; Donepezil; Double-Blind Method; Drug Therapy, Combination; Haloperidol; Humans; Indans; Piperidines; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Individuals who have Mild Cognitive Impairment (MCI) may be in a transitional stage between aging and Alzheimer's disease (AD). The high rate of conversion from MCI to AD makes early treatment an important clinical issue. Recent evidence suggests that cognitive training intervention may reduce the rate of progression to AD.. To evaluate the efficacy of a NeuroPsychological Training (TNP) in patients with MCI who are treated with cholinesterase inhibitors (ChEIs), compared with patients MCI treated only with ChEIs and patients not treated, in a longitudinal, one year follow-up study.. One year longitudinal and retrospective comparison study of neuropsychological performances in 59 subjects affected by Mild Cognitive Impairment (MCI) according to Petersen's criteria. Fifteen subjects were randomised to receive TNP plus cholinesterase inhibitors; 22 subjects cholinesterase inhibitors alone and 22 subjects no treatment. All the subjects referring memory complaints, corroborated by an informant, underwent a multidimensional assessment concerning neuropsychological, behavioural and functional characteristics, at baseline and after one year follow-up.. Subjects without treatment maintained their cognitive, functional and behavioural status after one year; patients treated only with ChEIs improved in depressive symptoms whereas subjects treated with TNP and ChEIs showed significant improvements in different cognitive areas, such as memory, abstract reasoning and in behavioural disturbances, particularly depressive symptoms.. A long-term TNP in ChEIs-treated MCI subjects induces additional cognitive and mood benefits.

Topics: Activities of Daily Living; Aged; Cholinesterase Inhibitors; Cognition Disorders; Combined Modality Therapy; Computer-Assisted Instruction; Donepezil; Female; Galantamine; Humans; Indans; Intelligence; Longitudinal Studies; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Nootropic Agents; Orientation; Phenylcarbamates; Piperidines; Problem Solving; Retrospective Studies; Rivastigmine; Software; Treatment Outcome

Individuals diagnosed as having mild cognitive impairment (MCI) have a high likelihood of progressing to dementia within 3 to 5 years, but not all individuals with MCI progress to dementia. Prognostic uncertainty suggests the need for additional measures to assist the clinician.. To assess the added value of qualitative measures of medial temporal atrophy (MTA) to estimate the relative risk of progressing from MCI to dementia.. A 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study initially designed to evaluate the efficacy of donepezil hydrochloride or vitamin E vs placebo to delay progression of MCI to dementia.. Memory assessment centers.. A total of 190 individuals with MCI.. Ratings of MTA performed using magnetic resonance images obtained at baseline. Log-rank tests and Cox proportional hazards ratios examining the significance of MTA estimates in predicting progression of MCI to dementia.. A mean MTA score greater than 2.0 was associated with a greater than 2-fold increased likelihood of progression to dementia during the observation period (hazards ratio, 2.30; 95% confidence interval, 1.09-4.92; P = .03) after controlling for age, education, sex, and baseline Mini-Mental State Examination score.. Adjusted estimates of MTA were associated with significantly increased risk of developing dementia within 3 years, suggesting that obtaining a magnetic resonance image during the evaluation of MCI may offer additional independent information about the risk of progression to dementia. Given the relatively high prevalence of MCI in the general population, use of this method as part of routine clinical evaluation may help identify individuals who might benefit from increased surveillance and future treatment.. clinicaltrials.gov Identifier: NCT00000173.

Topics: Aged; Aged, 80 and over; Atrophy; Cognition Disorders; Dementia; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Predictive Value of Tests; Reproducibility of Results; Temporal Lobe; Vitamin E

To investigate the neurocognitive measures that best predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD).. We evaluated 539 participants with aMCI from the Alzheimer's Disease Cooperative Study clinical drug trial of donepezil, vitamin E, or placebo. During the study period of 36 months, 212 aMCI participants progressed to AD. Using progression from aMCI to AD within 36 months as the dependent variable, a generalized linear model was fit to the data using the least absolute shrinkage and selection operator. Independent variables included in this analysis were age, sex, education, APOE-e4 (APOE4) status, family history of dementia, Mini-Mental State Examination score, Digits Backwards (Wechsler Memory Scale), Maze Time and Errors, Number Cancellation, Delayed Recall of Alzheimer's Disease Assessment Scale Word List, New York University Paragraph Recall Test (Immediate and Delayed), Boston Naming Test, Category Fluency, Clock Drawing Test, and the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog).. The model that best predicted progression from aMCI to AD over 36 months included APOE4 status, the Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), and the ADAS-cog total score. When APOE4 was removed from the analysis the resulting model had a similar estimated predictive accuracy as the full model. As determined by cross-validation, the estimated predictive accuracy of the final model was 80%.. Progression from amnestic mild cognitive impairment to Alzheimer disease in this cohort was best determined by combining four common, easily administered, cognitive measures.

Topics: Age Distribution; Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Antioxidants; Apolipoprotein E4; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Disease Progression; Donepezil; Female; Genotype; Humans; Indans; Linear Models; Male; Neuropsychological Tests; Piperidines; Placebo Effect; Predictive Value of Tests; Prognosis; Sex Distribution; Vitamin E

To determine whether an acetylcholinesterase inhibitor, such as donepezil, would improve memory or other cognitive/psychological functions in epilepsy patients with subjective memory complaints.. Twenty-three epilepsy patients with subjective memory difficulty were randomized to either 3 months of donepezil (10 mg/day) or 3 months of placebo treatment, and then crossed over to the other treatment arm. Patients and physicians were blinded to treatment phase throughout data acquisition. Assessment of memory and other cognitive functions, subjective memory, mood, and self-rated quality of life (QOL) and social functioning was performed at baseline and following completion of both treatment phases. Seizure frequency and severity as well as treatment emergent adverse effects were also monitored.. Donepezil treatment was not associated with improvement in memory or other cognitive functions, mood, social functioning or QOL. Comparable increases in self-rated memory functioning relative to baseline were evident during donepezil and placebo phases. Donepezil treatment was not associated with increased seizure frequency or severity. Similar to group results, analysis of change within individual patients as a function of treatment phase also showed neither significant benefit nor detriment associated with donepezil.. This study found no benefit on memory or other cognitive/psychological functions in a heterogeneous group of epilepsy patients with subjective memory difficulty. Further investigation would be required to determine whether individual patients, or those with particular epilepsy syndromes, might benefit from donepezil or other acetylcholinesterase inhibitors, or if a higher dosage might be effective.

Topics: Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy; Health Status; Humans; Indans; Memory Disorders; Neuropsychological Tests; Piperidines; Placebos; Quality of Life; Severity of Illness Index; Social Adjustment; Treatment Outcome

To examine whether the presence of domain-specific cognitive impairments would predict a response to donepezil medication in patients with mild-to-moderate Alzheimer disease (AD).. The protocol was an open-label study of 30 AD subjects (mean age 74 years; education 11 years; Mini-Mental State Exam (MMSE) 23 of 30) beginning a 6-month course of treatment with donepezil. Global response to treatment was determined using a combination algorithm based on changes over 6 months in the ADAS-cog, MMSE and CIBIC. In addition, a set of neuropsychological and experimental cognitive tests designed to test five domains of cognition were administered before beginning therapy in order to determine which domain of testing would be predictive to response to treatment. The tests examined attention, short-term and working memory, learning and memory, visuo-spatial motor skills, and lexical-semantic knowledge.. Eighteen of the thirty subjects were rated as having responded (stable or improved scores on the combination algorithm) to the therapy. Responders were significantly less impaired prior to treatment on the following tests: the Clock Drawing Test, a Visual-Spatial Motor Tracking Test, and the Boston Picture Naming Test. No significant initial group differences were noted on the other neuropsychological or experimental cognitive measures.. The tests that most reliably predicted response to donepezil in AD subjects were in the domains of visual-spatial motor abilities and lexical-semantic functioning.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Predictive Value of Tests; Prospective Studies; Severity of Illness Index

To study the effect of donepezil in treating patients with cognitive decline following coronary artery bypass graft (CABG) surgery.. Forty-four patients, with at least a 0.5 SD decline at 1 year post-CABG on at least one cognitive domain compared to their pre-CABG baseline score, were randomized to treatment with donepezil (titrated to 10 mg daily) or placebo in a 12-week double-blind, single center, randomized study. A composite cognitive change score served as the primary outcome. Secondary outcome measures included tests of memory, attention, psychomotor speed, and executive function.. The composite cognitive outcome did not show significant treatment effects. Secondary measures varied in their sensitivity to donepezil effects with the largest effects seen on the Wechsler Visual Memory Scale-Delayed and Immediate recall tests. More than twice (52% vs. 22%) as many donepezil-treated patients showed a significant improvement compared with placebo patients on Delayed recall. Tests with weak effect sizes and minimal trends favoring donepezil were the Boston Naming and Digit Symbol. However, most of the other instruments (e.g., Digit Span, Trails B, and Controlled Word Association) showed no treatment benefits. More donepezil-treated than placebo-treated patients experienced diarrhea, but other adverse effects and safety measures did not differ between groups.. In the post-CABG mild cognitive decline setting, donepezil did not improve composite cognitive performance but improved some aspects of memory. Donepezil was well tolerated and had no significant effects on EKG parameters. Because of limitations such as small sample size and multiplicity of tests, these findings are preliminary but add to our knowledge of cholinergic effects in vascular mild cognitive decline.

Topics: Aged; Cardiopulmonary Bypass; Cognition Disorders; Coronary Artery Bypass; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Female; Follow-Up Studies; Humans; Indans; Male; Memory, Short-Term; Mental Recall; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Postoperative Complications; Wechsler Scales

To evaluate the efficacy and safety of donepezil for severe Alzheimer disease (AD).. Patients with severe AD (Mini-Mental State Examination [MMSE] scores 1 to 12 and Functional Assessment Staging [FAST] scores > or =6) were enrolled in this multinational, double-blind, placebo-controlled trial at 98 sites. Patients were randomized to donepezil 10 mg daily or placebo for 24 weeks. Primary endpoints were the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus). Secondary endpoints included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), and the Resource Utilization for Severe Alzheimer Disease Patients (RUSP). Efficacy analyses were performed in the intent-to-treat (ITT) population using last post-baseline observation carried forward (LOCF). Safety assessments were performed for patients receiving > or =1 dose of donepezil or placebo.. Patients were randomized to donepezil (n = 176) or placebo (n = 167). Donepezil was superior to placebo on SIB score change from baseline to endpoint (least squares mean difference 5.32; p = 0.0001). CIBIC-Plus and MMSE scores favored donepezil at endpoint (p = 0.0473 and p = 0.0267). Donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP. Adverse events reported were consistent with the known cholinergic effects of donepezil and with the safety profile in patients with mild to moderate AD.. Patients with severe AD demonstrated greater efficacy compared to placebo on measures of cognition and global function.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Placebos; Recovery of Function; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Cognitive dysfunction is common in schizophrenia and linked with psychosocial dysfunction. We examined the possible effect of a 16-week trial of donepezil on cognition in young persons with stable schizophrenia.. Twenty-six outpatients who met criteria for age, duration of illness, clinical stability, and medications were randomly assigned to 16-week treatment with donepezil or placebo using a double blind design. At beginning and conclusion of the trial, participants completed standardised computerised assessment of neurocognition and social cognition. Symptomatology and functioning were assessed using standard rating scales for negative and positive symptoms, depression and mania, and quality of life.. No treatment effects were found on any cognitive functions or clinical symptoms in placebo or donepezil groups.. Similar to other studies using acetylcholinesterase inhibitors in more heterogeneous and symptomatic groups of patients with schizophrenia, donepezil does not appear to enhance cognitive abilities. Persistent cognitive impairment in schizophrenia with pervasive effects on psychosocial functioning and outcome, urge the search for agents that may offer improvement.

Topics: Adult; Brain; Brief Psychiatric Rating Scale; Cholinesterase Inhibitors; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Schizophrenia; Severity of Illness Index; Social Perception

Oxidative stress and neuronal energy depletion are characteristic biochemical hallmarks of Alzheimer's disease (AD). It is therefore conceivable that pro-energetic and antioxidant drugs such as alpha-lipoic acid might delay the onset or slow down the progression of the disease. In a previous study, 600mg alpha-lipoic acid was given daily to nine patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of 12 months. The treatment led to a stabilization of cognitive functions in the study group, demonstrated by constant scores in two neuropsychological tests (the mini mental state exam, MMSE and the Alzheimer's disease assessment score cognitive subscale, ADAScog). In this report, we have extended the analysis to 43 patients over an observation period of up to 48 months. In patients with mild dementia (ADAScog < 15), the disease progressed extremely slowly (ADAScog: +1.2 points/year, MMSE: -0.6 points/year), in patients with moderate dementia at approximately twice the rate. However, the progression appears dramatically lower than data reported for untreated patients or patients on choline-esterase inhibitors in the second year of long-term studies. Despite the fact that this study was not double-blinded, placebo-controlled and randomized, our data suggest that treatment with alpha-lipoic acid might be a successful 'neuroprotective' therapy option for AD. However, a state-of-the-art phase II trial is needed urgently.

Topics: Aged; Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Female; Follow-Up Studies; Galantamine; Humans; Indans; Long-Term Care; Male; Mental Status Schedule; Middle Aged; Oxidative Stress; Piperidines; Thioctic Acid

Perimenopausal and menopausal women are more likely to complain of memory loss than are premenopausal women, although the association between menopause and cognitive loss remains controversial. Recently published studies on the risks of hormone therapy have left many women and their physicians seeking effective nonhormonal treatments for menopausal symptoms, including cognitive loss.. This study investigated the efficacy of the cholinesterase agent donepezil in the treatment of menopause-related cognitive loss.. Community-dwelling women in natural menopause were recruited for a randomized, double-blind, placebo-controlled study of donepezil. To qualify for enrollment, the Brief Cognitive Rating Scale was used to determine cognitive symptoms, and women with depression were excluded. Subjects were randomized to receive either donepezil, commencing at 5 mg/d, or placebo. At week 6 of randomization, the dosage of donepezil was increased to 10 mg/d. Treatment continued throughout the 26-week study. The primary outcome measure was the overall change in neurocognitive test results over time. Outcome variables of test scores were analyzed before and after receipt of donepezil or placebo.. A total of 28 women aged 46 to 60 years were enrolled. Fourteen women were randomized to receive active drug, 14 to placebo. Two women dropped out of the placebo group. There were no statistically significant differences between treatment groups in post-/pre-dose mean score ratios. No interactions were statistically significant. The P values for tests of equal variances did not reveal a difference in the means. Subjective measures did show some trends toward improvement in memory and cognition.. Donepezil was no more effective than placebo in treating the symptoms of menopause- related memory and cognitive loss.

Topics: Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Memory Disorders; Menopause; Middle Aged; Piperidines; Treatment Outcome

Cognitive impairment and negative signs are common in patients with schizophrenia. Up to 35% of elderly patients with schizophrenia fulfill the diagnostic criteria of dementia. Donepezil inhibits cholinesterase, thus enhancing cholinergic neurotransmission. We tested the efficacy of donepezil in elderly patients with chronic schizophrenia and severe cognitive impairment.. Following baseline assessment, patients were randomly assigned to receive either donepezil or placebo. The dose was 5 mg daily for the first week and 10 mg for an additional 11 weeks. The procedure was repeated using the crossover compound. The Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI) and Alzheimer Disease Assessment Scale - Cognitive subscale (ADAS-Cog) were used to assess the severity of symptoms, cognitive status and intervention effects.. Twenty subjects were enrolled (15 females, five males), mean age 70.2 years (SD 6.5) and mean duration of disease 38.5 years (SD 9.3). A modest treatment effect was found for both placebo and donepezil treatment periods. No crossover effect was found. No statistical differences were demonstrated between the two treatment groups (CGI p = 0.37, PANSS p = 0.71, ADAS-Cog p = 0.86). Two patients died during the study period due to unrelated causes and one patient discontinued participation due to increased agitation.. Donepezil does not seem to improve negative signs and cognitive impairment in elderly patients with chronic schizophrenia.

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Chronic Disease; Cognition Disorders; Comorbidity; Cross-Over Studies; Dementia; Depressive Disorder; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Delays in the diagnosis of Alzheimer's disease, and, therefore, delays in treatment, may have a detrimental effect on a patient's long-term well-being. This study assessed the effects of postponing donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer's disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer's disease. These data support the long-term efficacy and safety of donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Drug Administration Schedule; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Topics: Alzheimer Disease; Cognition Disorders; Donepezil; Humans; Indans; Long-Term Care; Piperidines; Treatment Outcome; Vitamin E

A prospective, open-label phase II study was conducted to determine whether donepezil, a US Food and Drug Administration-approved reversible acetylcholinesterase inhibitor used to treat mild to moderate Alzheimer's type dementia, improved cognitive functioning, mood, and quality of life (QOL) in irradiated brain tumor patients.. Thirty-four patients received donepezil 5 mg/d for 6 weeks, then 10 mg/d for 18 weeks, followed by a washout period of 6 weeks off drug. Outcomes were assessed at baseline, 12, 24 (end of treatment), and 30 weeks (end of wash-out). All tests were administered by a trained research nurse.. Of 35 patients who initiated the study, 24 patients (mean age, 45 years) remained on study for 24 weeks and completed all outcome assessments. All 24 patients had a primary brain tumor, mostly low-grade glioma. Scores significantly improved between baseline (pretreatment) and week 24 on measures of attention/concentration, verbal memory, and figural memory and a trend for verbal fluency (all P < .05). Confused mood also improved from baseline to 24 weeks (P = .004), with a trend for fatigue and anger (all P < .05). Health-related QOL improved significantly from baseline to 24 weeks, particularly, for brain specific concerns with a trend for improvement in emotional and social functioning (all P < .05).. Cognitive functioning, mood, and health-related QOL were significantly improved following a 24-week course of the acetylcholinesterase inhibitor donepezil. Toxicities were minimal. We are planning a double blinded, placebo-controlled, phase III trial of donepezil to confirm these favorable results.

Topics: Adult; Affect; Aged; Anger; Brain Neoplasms; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Fatigue; Female; Glioma; Humans; Indans; Male; Memory; Middle Aged; Piperidines; Prospective Studies; Quality of Life; Radiation Injuries

Current outcome measures for Alzheimer's disease (AD) drugs have been criticized as insufficiently patient-centred. One commonly unmeasured goal of patients and caregivers is verbal repetition.. We examined how often reducing repetition (of questions, statements or stories) was set as treatment goal, whether and when it responded, and how change in repetition correlated with change in other domains.. This is a secondary analysis of the open-label Atlantic Canada Alzheimer's Disease Investigation of Expectations study of donepezil for mild-moderate AD in 100 community-dwelling people. Goal Attainment Scaling, an individualized account of the goals of treatment, was the primary outcome measure.. Reducing repetition was a treatment goal in 46%, who were not systematically different from others. Of 18 patients in whom repetition improved for 9 months, 83% (15) showed a response at 3 months. Early (3-month) response correlated best with the overall level of goal attainment (r = 0.74) and changes in leisure activities (r = 0.69) and social interactions (r = 0.68) compared with changes in cognition (r = 0.44) or behaviour (r = 0.11). Correlations with the ADAS-Cog and MMSE change scores remained only modest (at 12 months = -0.25 and 0.19, respectively). Correlations with the CIBIC-Plus were higher (-0.47 at 3 months and -0.43 at 12 months).. Diminution of repetition is common, and appears to mark response to cholinesterase inhibition in some patients. Responders generally also show improved cognition and function, perhaps as an aspect of improved executive function.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Memory, Short-Term; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome; Verbal Behavior

Cerebral blood flow (CBF) was assessed during a verbal recall task using [(15)O]water positron emission tomography (PET) in older adults with mild cognitive deficits participating in a placebo-controlled donepezil trial. The placebo group demonstrated reduced CBF in the left frontal and temporal regions over the 6-month period, while those receiving donepezil did not. The placebo group's performance did not change on a list-learning task, while the donepezil group's performance improved, despite having had lower performance at intake. These findings suggest that donepezil treatment may be associated with a relative maintenance of CBF and improved list-learning.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Blood Flow Velocity; Brain; Cerebral Cortex; Cognition Disorders; Dominance, Cerebral; Donepezil; Double-Blind Method; Female; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Positron-Emission Tomography; Regional Blood Flow

The article mentions the conclusions of most evidential works investigating donepezil in the treatment of cognitive deficit in schizophrenia. It focuses on an analysis of a sub-group of 20 patients receiving treatment of the donepezil in an extended Czech double-blind placebo controlled study.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Cognition Disorders; Czech Republic; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory; Middle Aged; Neuropsychological Tests; Piperidines; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Striatal cholinergic dysfunction may be important in Huntington disease (HD). We studied whether donepezil improves chorea, cognition, and quality of life (QoL) in HD. Thirty patients were randomly assigned to treatment with donepezil or placebo. At the doses studied, donepezil did not improve chorea, cognition, or QoL. Adverse events were similar between both groups. Based on this small sample study, donepezil was not an effective treatment for HD.

Topics: Chorea; Cognition Disorders; Donepezil; Female; Humans; Huntington Disease; Indans; Male; Middle Aged; Nootropic Agents; Outcome Assessment, Health Care; Piperidines; Placebo Effect; Quality of Life; Recovery of Function; Treatment Outcome

A Phase II, 4-week randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and efficacy of the Ampakine compound CX516 as a potential treatment for the underlying disorder in fragile X syndrome (FXS). After baseline screening, subjects with FXS (n = 49) underwent a 1-week placebo lead-in and then were randomized to study drug or placebo for a 4-week period. Cognitive and behavioral outcome measures were administered prior to treatment, at the end of treatment, and 2 weeks posttreatment. There were minimal side effects, no significant changes in safety parameters, and no serious adverse events. There was a 12.5% frequency of allergic rash in the CX516 group and 1 subject developed a substantial rash. There was also no significant improvement in memory, the primary outcome measure, or in secondary measures of language, attention/executive function, behavior, and overall functioning in CX516-treated subjects compared to placebo. This study did demonstrate that many outcome measures were reproducible in this test-retest setting for the FXS population, yet some were too difficult or variable. Adult subjects with FXS were able to complete an intensive clinical trial, and some valid outcome measures were identified for future FXS trial design. Problems with potency of CX516 in other studies have suggested dosing may have been inadequate for therapeutic effect and thus it remains unclear whether modulation of AMPA-mediated neurotransmission is a viable therapeutic strategy for the treatment of FXS.

Topics: Adolescent; Adult; Autistic Disorder; Child Behavior Disorders; Cognition Disorders; Dioxoles; Dose-Response Relationship, Drug; Double-Blind Method; Drug Eruptions; Female; Fragile X Syndrome; Humans; Long-Term Potentiation; Male; Neuronal Plasticity; Neuropsychological Tests; Personality Assessment; Piperidines; Receptors, AMPA; Synaptic Transmission; Treatment Outcome

Up to 90% of small cell lung cancer (SCLC) patients suffer cognitive dysfunction. Since donepezil and vitamin E have been somewhat successful in treating other dementias, this study tested the hypothesis that these agents can prevent cognitive decline in SCLC patients. Because accrual was poor, this trial also offered opportunities for suggesting other study designs for future clinical trials on cognitive dysfunction in this group of patients.. This double blind, placebo controlled trial tested oral donepezil 5 mg/day (with dose escalation to 10 mg after 1 month) and oral vitamin E 1,000 IU/day in SCLC patients after completion of all cancer therapy, including prophylactic cranial irradiation (PCI). Cognition, adverse events, and quality of life were assessed throughout the study period.. Only nine of 104 patients enrolled over 15 months (four donepezil and vitamin E-treated versus five placebo-exposed), and thus no definitive conclusions could be drawn. Nonetheless, the only patient who manifested a precipitous decline in cognition was taking donepezil and vitamin E. There was also a slight trend of increased gastrointestinal side effects among donepezil and vitamin E-treated patients. There were no notable differences in cognitive stability, adverse events, or quality of life between treatment arms.. These preliminary findings do not provide enthusiasm for testing donepezil and vitamin E in the manner undertaken here for preventing cognitive dysfunction in SCLC patients. Eligibility criteria and timing of trial intervention are discussed as potential impediments to successful trial completion.

Topics: Aged; Antioxidants; Carcinoma, Small Cell; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Lung Neoplasms; Male; Piperidines; Vitamin E

Theoretically, central acetylcholinesterase inhibitors (CAIs) could alleviate at least some of the main symptoms of chronic traumatic brain injury (TBI). The aim of this report is to describe clinical experience of the treatment of chronic TBI with these drugs.. From an outpatient clinic material, 111 patients were selected having chronic stable TBI with at least one of the following target symptoms: fatigue, poor memory, diminished attention or diminished initiation. Patients received in random donepezil, galantamine or rivastigmine. The evaluation of the treatment response was based on the subjective view of the patient.. As first treatment, 27 patients received donepezil, 30 galantamine and 54 rivastigmine. Altogether 41 patients tried more than one drug, but only three patients tried all three alternatives. In total, 61% of patients had a marked positive response and 39% a modest or no response. The clearest effect was in almost all responders a better vigilance and attention causing better general function. About half of the patients (55%) wanted to continue therapy with one of these drugs. The therapeutic response became very quickly and at low doses. There were no significant differences between the three drugs either in effect or tolerability. The age, sex, type of injury, severity of TBI or elapsed time after injury did not affect the response. The mean dose in maintenance therapy was 7.2 mg od for donepezil, 5.0 mg bid for galantamine and 2.3 mg bid for rivastigmine. Side effects or inadequate therapeutic response were the main causes for discontinuation with nearly equal frequency. Paradoxical responses were seen in some patients.. CAIs show a very promising therapeutic potential in the treatment of chronic TBI. There were no significant differences between the three drugs. Large-scale randomised double-blinded placebo-controlled studies are clearly needed.

Topics: Adolescent; Adult; Aged; Brain Damage, Chronic; Brain Injuries; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Galantamine; Humans; Indans; Male; Middle Aged; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Psychomotor Performance; Rivastigmine; Treatment Outcome

To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy.. Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy.. Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05).. Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Attention; Cerebral Cortex; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Piperidines; Positron-Emission Tomography

Schizophrenia is a disorder with cognitive deficits that could stem from cholinergic dysfunction.. Our aim was to examine if donepezil administered to stable, medicated outpatients with schizophrenia improves cognition and psychopathology.. We conducted a double-blind placebo-controlled trial of donepezil up to 10 mg/day added for 8 weeks to ongoing antipsychotic treatment in 36 typical community-treated schizophrenia patients not selected for cognitive impairment.. Donepezil did not improve measures of cognition or psychopathology. It was well tolerated.. Consistent with other studies, addition of donepezil to stable patients with schizophrenia did not improve cognition or measures of psychopathology. This result does not support the hypothesis that residual symptoms and cognitive problems result from a cholinergic deficit that can be remedied by an acetylcholinesterase inhibitor. A donepezil add-on strategy might make sense in selected schizophrenia cases where a pathological process is known to affect cholinergic neurons (e.g., history of head injury or comorbid dementia).

Topics: Capsules; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Dyskinesias; Female; Humans; Indans; Male; Middle Aged; Piperidines; Placebos; Schizophrenia; Sialorrhea; Time Factors; Treatment Outcome

Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease.. In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function.. A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers.. Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.

Topics: Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Double-Blind Method; Humans; Indans; Nootropic Agents; Piperidines; Proportional Hazards Models; Treatment Failure; Vitamin E

The purpose was to identify vascular influences on the responsiveness to donepezil chloride. The study included 50 untreated probable Alzheimer's disease patients with the Modified Hachinski Ischemic Score <4. We assessed baseline cognitive status using the Revised Hasegawa Dementia Scale (HDS-R), Clinical Dementia Rating (CDR) and the clock drawing test (CDT). The response to 5 mg of donepezil was monitored by the CDT for 12 months. Patients were classified as true responders (TR), unchanged (UC) and non-responders according to changes on the CDT in response to treatment. High HDS-R scores, low CDT scores, low CDR and presence of hypertension (HBP) and periventricular hyperintensities (PVH) predicted a TR- or UC-type outcome. Aggravation of executive function by HBP and/or PVH and its improvement by donepezil may have been detected by the CDT.

Topics: Aged; Alzheimer Disease; Brain; Brain Ischemia; Cholinesterase Inhibitors; Cognition Disorders; Demography; Donepezil; Double-Blind Method; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Piperidines; Risk Factors; Severity of Illness Index

To characterise the population of Alzheimer's disease patients treated with acetylcholinesterase inhibitors, to analyse effectiveness and drug safety in the clinical practice, and to identify variables that may predict the response to therapy.. From September 2000 to December 2001, a total of 5,462 patients diagnosed with mild to moderate Alzheimer's disease were enrolled at the time of their first prescription of the study drugs and followed up for an average of 10.5 months. Responders were defined as patients with a mini-mental state examination (MMSE) score improvement of 2 or more points from baseline after 9 months of therapy.. At 9 months, 2,853 patients (52.2%) completed the study. The mean change from baseline in MMSE scores was an improvement of 0.5 points (+/-3.0). The proportion of responders to the therapy was 15.7% at 9 months. A greater probability of response at 9 months was observed among patients without concomitant diseases at baseline [odds ratio (OR)=2.1, 95% confidence interval (CI) 1.5-2.9] and among those with a response at 3 months (OR=20.6, 95% CI 17.2-24.6). During the study period, 285 patients (5.2%) discontinued the treatment because of an adverse drug reaction.. Effectiveness of acetylcholinesterase inhibitors on cognitive symptoms of patients with mild to moderate Alzheimer's disease is modest. At 9 months, improvement was evident only in a subgroup of patients without concomitant diseases and who had demonstrated a response at 3 months.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Donepezil; Female; Follow-Up Studies; Galantamine; Humans; Indans; Italy; Male; Middle Aged; Phenylcarbamates; Piperidines; Rivastigmine; Time Factors; Treatment Outcome

Topics: Aged; Cholinesterase Inhibitors; Cognition Disorders; Confidence Intervals; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Neuropsychological Tests; Piperidines; Retrospective Studies; Treatment Outcome; Vitamin E

Although there have been several case reports suggesting the beneficial effect of acetylcholinesterase inhibitors in the cognitive deficits seen in schizophrenia, controlled studies have revealed contradictory results. The aim of this study was to investigate if donepezil could improve cognitive functions in schizophrenia. Twelve schizophrenic patients, who were diagnosed according to DSM-IV criteria and who had been on a stable dose of a high-potency typical antipsychotic for a minimum period of 3 months, participated in this 12-wk double-blind, placebo controlled, cross-over study of donepezil adjunctive treatment. Patients were randomly assigned under double-blind conditions to receive 5 mg/d donepezil or placebo for 6 wk, and then were crossed over to the alternate condition for 6 additional weeks. At baseline, 6 and 12 wk, patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, the Wechsler Memory Scale Revised (WMS-R), a test for Verbal Fluency, Trail Making Test, Parts A and B, and Wisconsin Card Sorting Test (WCST). Treatment effect was not significant in any of the cognitive measures. There were also no significant changes in the PANSS and depression scores. Nicotinic receptor desensitization may cause non-responsiveness to acetylcholine as previously suggested, but the most likely explanation appears to be that defects in other neurotransmitter systems account for the cognitive deficits seen in schizophrenic patients.

Topics: Adult; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

We compared the effect of S(+)-ketamine to remifentanil, both in combination with propofol, on the neurocognitive outcome after open-heart surgery in 106 patients. A battery of neurocognitive tests was administered before surgery and 1 and 10 wk after surgery. Fourteen patients (25%) in the control group and 10 patients (20%) in the S(+)-ketamine group had 2 or more tests with a cognitive deficit (decline by at least one preoperative SD of that test in all patients) 10 wk after surgery (P = 0.54). Z-scores were calculated for all tests. No significantly better performance could be detected in the S(+)-ketamine group, except for the Trailmaking B test 10 wk after surgery. We conclude that S(+)-ketamine offers no greater neuroprotection compared with remifentanil during open-heart surgery.. N-methyl-D-aspartic acid receptors play an important role during ischemic brain injury. We could not demonstrate that S(+)-ketamine resulted in greater neuroprotective effects compared with remifentanil during cardiopulmonary bypass procedures when both were combined with propofol.

Topics: Aged; Cardiopulmonary Bypass; Chi-Square Distribution; Cognition Disorders; Female; Humans; Ketamine; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Pain, Postoperative; Piperidines; Propofol; Prospective Studies; Remifentanil

Clinical trials have demonstrated the efficacy of cholinesterase inhibitors (ChEI) in improving cognitive status and disability in subjects with mild to moderate Alzheimer's disease (AD). However, little is known about the effectiveness of ChEI in clinical practice, and no large clinical trials comparing different ChEI are available at present. Aim of this study was to evaluate safety and effectiveness of ChEI in a sample of elderly outpatients diagnosed with mild to moderate AD. We selected 407 subjects for ChEI treatment (donepezil,rivastigmine or galantamine). Their cognitive function was evaluated by means of the mini mental state examination (MMSE), and the global functional status was estimated by using the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales at baseline (To), then after 1 (T1), 3 (T2) and 9 months (T3), respectively. T3 follow-up was completed by 212 subjects. The patients were considered as responders (R), if the MMSEscore at T2 was unchanged or improved, if compared to that of T0. In 35 patients (8.6 %)treatment was withdrawn because of mostly gastrointestinal adverse events. Compared to the other drugs, donepezil was associated with a lower incidence of withdrawals due to adverse events. Subjects who completed T3 follow-up (age 78 +/- 6 years, MMSE scores 18.8 +/- 3.9) showed an increase at T2 of 0.7 +/- 2.7 (p = 0.001) and a decrease at T3 of -0.6 +/- 3.4 (p = 0.008) in the MMSE scores, as compared to To . The ADL and IADL scores did not show significant changes at T2; however, both decreased significantly at T3. The patients Rat-T2 showed a better cognitive and functional outcome at T3 , compared to the nonresponders(NR-at-T2), displaying values of MMSE R-at-T2 0.4 +/- 3.1 vs. NR-at-T2 -3.0 +/- 2.5, p = 0.001, and ADL values of -0.3 +/- 1.2 vs. -0.7 +/- 1.3, p = 0.03, respectively. No significant difference was found in the changes of MMSE scores between donepezil and rivastigmine (galantamine was not included in the comparison due to the small number of treated subjects). In conclusion, in this sample of elderly subjects with mild to moderate AD,treated with ChEI, a small but significant decline in cognitive and functional status was observed after 9 months. Subjects who showed a good response to treatment after 3 months, had a better cognitive and functional outcome at 9 months. No significant difference in cognitive outcome was found between drugs, while donepezil was better tolerat

Topics: Aged; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Galantamine; Humans; Indans; Male; Neuropsychological Tests; Phenylcarbamates; Piperidines; Rivastigmine; Severity of Illness Index

To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI).. A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician's Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations.. Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient.. Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

To investigate whether variations within normal ranges of thyroid functioning are related to cognitive and neuropsychiatric functioning in Alzheimer disease (AD).. Mild alterations of thyroid hormone levels, even in the normal range, are associated with changes in mood and cognitive functioning in older, nondemented adults, and lower concentrations of thyroid hormones have been shown to be associated with an increased risk for cognitive decline. Less is known about the relationship between thyroid hormone levels and cognitive and neuropsychiatric dysfunction in AD.. Twenty-eight euthyroid patients with AD on donepezil underwent evaluation of thyroid status, including measures of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and cognitive and neuropsychiatric assessment with the Alzheimer's Disease Assessment Scale, Neuropsychiatric Inventory, and Visual Analog Mood Scales.. Correlational analyses indicated statistically significant associations between FT4 concentrations and self-reported feelings of fear and fatigue. Fear and fatigue were negatively correlated with FT4. There were no significant relationships between thyroid hormones and cognition and other depressive and anxiety symptoms.. Results of this preliminary study support a relationship between thyroid status and neuropsychiatric symptoms in euthyroid individuals with AD, with lower concentrations of FT4 associated with fear and fatigue.

Topics: Affective Symptoms; Aged; Alzheimer Disease; Cognition Disorders; Cross-Sectional Studies; Donepezil; Female; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Statistics, Nonparametric; Thyroid Function Tests; Thyrotropin; Thyroxine

To evaluate the efficacy of a cognitive-motor program in patients with early Alzheimer disease (AD) who are treated with a cholinesterase inhibitor (ChEI).. Patients with mild cognitive impairment (MCI) (12), mild AD (48), and moderate AD (24) (Global Deterioration Scale stages 3, 4, and 5) were randomized to receive psychosocial support plus cognitive-motor intervention (experimental group) or psychosocial support alone (control group). Cognitive-motor intervention (CMI) consisted of a 1-year structured program of 103 sessions of cognitive exercises, plus social and psychomotor activities. The primary efficacy measure was the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary efficacy measures were the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Geriatric Depression Scale. Evaluations were conducted at 1, 3, 6, and 12 months by blinded evaluators.. Patients in the CMI group maintained cognitive status at month 6, whereas patients in the control group had significantly declined at that time. Cognitive response was higher in the patients with fewer years of formal education. In addition, more patients in the experimental group maintained or improved their affective status at month 12 (experimental group, 75%; control group, 47%; p = 0.017).. A long-term CMI in ChEI-treated early Alzheimer disease patients produced additional mood and cognitive benefits.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cholinesterase Inhibitors; Cognition Disorders; Cognitive Behavioral Therapy; Combined Modality Therapy; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Patient Satisfaction; Patients; Phenylcarbamates; Physical Therapy Modalities; Piperidines; Psychomotor Disorders; Rivastigmine; Single-Blind Method; Treatment Outcome

A pilot study was conducted to examine if donepezil could enhance cognitive function in patients with schizophrenia. Fifteen subjects who were on stable olanzapine treatment were entered into a 6-week open-labeled trial of donepezil. Subjects received baseline and end-of-study P50 and neuropsychological assessments. Donepezil treatment resulted in significant improvement in manual dexterity. There were moderate improvements in verbal recall memory and visual memory and processing speed, with smaller changes in P50 and verbal recognition memory. There was no effect on an attention measure. There were no changes in either positive or negative symptoms. These results suggest that cholinergic tone modulation may enhance selective behavioral functions in patients with schizophrenia, but further study is required to delineate the full extent of the potential benefit of this approach.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cognition Disorders; Donepezil; Drug Therapy, Combination; Evoked Potentials; Female; Humans; Indans; Male; Memory; Nootropic Agents; Olanzapine; Pilot Projects; Piperidines; Pirenzepine; Schizophrenia

Brain acetylcholinesterase activity was determined in healthy controls and in patients with mild cognitive impairment and early Alzheimer's disease.. A specific acetylcholinesterase tracer, [methyl-(11)C]N-methyl-piperidyl-4-acetate ([(11)C]MP4A), and a three dimensional PET system with magnetic resonance coregistration were used for imaging.. There was a significant difference in the acetylcholinesterase activity in the hippocampus between the groups (p = 0.03), the mean (SD) acetylcholinesterase activity (k(3) values, min(-1)) being 0.114 (0.036) in controls, 0.098 (0.023) in mild cognitive impairment, and 0.085 (0.022) in Alzheimer's disease. The mini-mental state examination score showed no significant relation with acetylcholinesterase activity in any brain area in the combined mild cognitive impairment/Alzheimer group.. Hippocampal acetylcholinesterase activity is only slightly reduced in mild cognitive impairment and early Alzheimer's disease and so the value of in vivo acetylcholinesterase measurements in detecting the early Alzheimer process is limited.

Topics: Acetates; Acetylcholinesterase; Aged; Alzheimer Disease; Analysis of Variance; Brain; Carbon Radioisotopes; Cognition Disorders; Female; Hippocampus; Humans; Imaging, Three-Dimensional; Male; Middle Aged; Neuropsychological Tests; Piperidines; Predictive Value of Tests; Reference Values; Tomography, Emission-Computed

Centrally acting cholinesterase inhibitors (ChEIs) improve cognitive functions in Alzheimer's disease (AD) and other forms of dementia. Evaluation of treatment efficacy is based mainly on subjective assessment methods such as standardized neuropsychological tests. Therefore, an additional objective tool for the evaluation of drug response would be most helpful.Thirty-two patients suffering from dementia of several etiologies were treated with ChEIs (tacrine 19, donepezil 5, rivastigmine 8). Cognitive response was assessed pre ChEIs initiation (baseline) and after 26 weeks, as optimal tolerated doses were achieved and maintained (endpoint). Evaluation included repeated measurements of Mini Mental State Examination (MMSE), Alzheimer's disease assessment scale cognitive part (ADAS-cog) and P300. For statistical analysis we used ANOVA with repeated measures and Pearson correlation coefficient. Results demonstrated improvement of mean ADAS-cog by 2.0 points (from 29.4, n = 31 to 27.4, n = 29; p = 0.08) while MMSE remained almost unchanged (20.1, n = 29 to 19.8, n = 28). Mean P300 latency reduced significantly by 24 ms (from 383 +/- 7.9 msec, n = 32 to 359 +/- 7 msec, n = 32; p = 0.0001). However mean amplitudes did not change significantly from baseline to endpoint (13.5 +/- 6.2, n = 31 to 12.8 +/- 6.1, n = 31). Significant correlations were found between mean ADAS-cog and mean P300 latency at baseline and end-point (R = 0.485 p = 0.019, R = 0.626 p = 0.001 respectively, n = 23) and between mean MMSE and P300 latency at baseline and endpoint (R = -0.420 p = 0.046, R = -0.703 p < 0.001 respectively, n = 23). Our data suggests that P300 is a reliable instrument for assessment of cognitive response to ChEIs in demented patients.

Topics: Acetylcholine; Aged; Carbamates; Cerebral Cortex; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Electroencephalography; Event-Related Potentials, P300; Female; Humans; Indans; Male; Middle Aged; Phenylcarbamates; Piperidines; Prospective Studies; Reaction Time; Rivastigmine; Tacrine; Treatment Outcome

Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.

Topics: Adult; Antipsychotic Agents; Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Therapy, Combination; Humans; Indans; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Outpatients; Piperidines; Placebos; Schizophrenia; Treatment Outcome

Our goal in this study was to determine whether donepezil, an acetylcholinesterase inhibitor, would improve cognitive functioning in 19 subjects with Down syndrome and no dementia. They were assigned to either a donepezil or placebo group. Cognitive functioning and caregiver ratings were measured at baseline, 4 weeks, and 12 weeks. With the exception of one area (language), no improvement was noted in any of the cognitive subtests, behavioral scores, or caregiver ratings. Subjects in the donepezil group showed an improvement in language scores compared to subjects in the placebo group. The results suggest that donepezil may improve language performance in subjects with Down syndrome and no dementia, but further studies need to be done on a larger group to confirm this result.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Down Syndrome; Drug Administration Schedule; Female; Humans; Indans; Language Development Disorders; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

To understand the treatment goals of Alzheimer's disease (AD) patients, carers, and physicians; to estimate whether clinically important goals are met during treatment with donepezil; and to compare a measure of goal attainment with standard measures used to evaluate AD treatment.. In a 12 month phase IV trial, 108 patients with mild to moderate AD, their primary carers, and treating physicians set goals assigned to five domains, using Goal Attainment Scaling (GAS) as the primary outcome. Goal attainment was assessed quarterly. GAS scores were correlated with standard outcomes, including the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog), and the Clinician's Interview-Based Impression of Change-Plus (CIBIC-plus).. Physicians set fewer goals (342, mean (SD) per patient=3 (1)) than patients/carers (855, mean=9 (3)), particularly in leisure (20% by physicians compared with 76% by patients/carers), and social interaction (24% versus 49%). Physicians observed statistically significant improvement in global goal attainment for six months, and patients/carers for nine months. Patients/carers described consistent goal attainment, whereas physicians observed variable effects, such as decline in cognition but improved social interaction and behaviour. Physician global GAS scores correlated highly with the CIBIC-plus at weeks 12 (r= -0.82) and 52 (r=-0.80), but not with the ADAS-cog (r=0.12 and r=-0.45, respectively). Patient/carer global GAS scores correlated moderately with the physician's CIBIC-plus (week 12 r=-0.51; week 52 r=-0.56), and nominally with the ADAS-cog.. Patients/carers and physicians differ in their expectations and impressions of treatment effects. Clinically important changes correlated only modestly with psychometric tests. Attainment of treatment goals does not accord with a simplistic model in which successful AD treatment means that all declines uniformly improve.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Goals; Humans; Indans; Interpersonal Relations; Male; Neuropsychological Tests; Piperidines; Professional-Patient Relations; Prospective Studies; Psychometrics; Severity of Illness Index

Despite the beneficial effects of atypical antipsychotics on cognition, these improvements will not return most schizophrenic patients to normative standards of cognitive functioning. Therefore, other treatments need to be considered. Subtle changes in cholinergic function in schizophrenic patients provide the rationale to test the effectiveness of cholinesterase inhibitors in treating cognitive impairment in schizophrenia.. Given this, a 12-week, double-blind, placebo-controlled trial of donepezil (5 mg and 10 mg) as adjunctive treatment to risperidone was conducted in a total of 36 schizophrenic patients.. Neither the 5-mg nor 10-mg dose of donepezil produced significant improvements in any cognitive measure compared with placebo.. It is possible that nicotinic receptor desensitization produced by chronic tobacco use in these patients rendered their nicotinic receptors refractory to the effects of increased agonist activity produced by donepezil. An alternative treatment is the allosterically potentiating ligands, which enhance the activity of (sensitize) nicotinic receptors in the presence of acetylcholine.

Topics: Adult; Aged; Antipsychotic Agents; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

To study the safety and efficacy of the cholinesterase inhibitor donepezil in patients with Parkinson's disease (PD) and cognitive impairment.. This was a double blind, randomised and placebo controlled, crossover study in which 14 patients with PD and cognitive impairment received donepezil (5 or 10 mg per day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the mini mental state examination (MMSE) score, the clinician's interview based impression of change plus caregiver input (CIBIC+) score, and the motor subscale of the unified Parkinson's disease rating scale (UPDRS).. Two patients on donepezil (14%) dropped out after one and four weeks of the first treatment period because of peripheral cholinergic side effects, otherwise the adverse effects were few and not severe. Carryover or residual effects were not observed. Parkinsonism did not increase during donepezil treatment. After 10 weeks of treatment, the mean MMSE score was increased by 2.1(SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC+ score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE (p=0.013) and CIBIC+ (p=0.034). Five (42%) patients on donepezil and two (17%) on placebo were rated as improved on the basis of the CIBIC+ score.. Donepezil improves cognition, and seems to be well tolerated and not to worsen parkinsonism in patients with cognitive impairment.

Topics: Administration, Oral; Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Parkinson Disease; Piperidines; Treatment Outcome

To evaluate the effect of 3 month therapy with donepezil, a centrally acting cholinesterase inhibitor, on cognitive performances, motor function and daily living activities in progressive supranuclear palsy (PSP).. Six patients with a diagnosis of PSP were evaluated at baseline and after 3 months of treatment with donepezil, 10 mg given at bedtime. Cognitive functions, motor symptoms and daily activities were evaluated by means of appropriate rating scales.. Donepezil was not effective on cognitive dysfunction and did not change ratings of daily living. Parkinsonian symptoms were unaffected by donepezil treatment.. Cholinergic replacement therapy alone is not likely to improve symptoms in a disorder characterized by a more widespread impairment of monoaminergic systems. Larger studies may be necessary to confirm the lack of effect of donepezil in this disorder.

Topics: Aged; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Severity of Illness Index; Supranuclear Palsy, Progressive

Cognitive impairment in multiple domains is common in patients with schizophrenia and may be a powerful determinant of poor functional ability and quality of life. We report a double-blind, placebo-controlled, cross-over study of donepezil augmentation in a schizoaffective disorder patient stabilized on olanzapine pharmacotherapy. The patient showed significant improvements in several cognitive measures and increased activation of prefrontal cortex and basal ganglia on functional MRI during the donepezil augmentation. In addition, the donepezil augmentation resulted in a reduction of depressive symptoms and in significant improvements in functional abilities and quality of life. Further studies of donepezil augmentation of neuroleptics in schizophrenia are warranted.

Topics: Adult; Basal Ganglia; Benzodiazepines; Brain; Brain Mapping; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Therapy, Combination; Humans; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Olanzapine; Piperidines; Pirenzepine; Prefrontal Cortex; Psychiatric Status Rating Scales; Psychotic Disorders; Quality of Life

Cognitive dysfunction occurs in up to 65% of patients with multiple sclerosis (MS), but there is no effective treatment for the symptoms. The authors conducted a 12-week, open-pilot study to assess the efficacy and tolerability of donepezil HCl administered in patients with MS and cognitive impairment. Seventeen patients at a long-term care facility with Mini-Mental State Examination scores of < or = 25 received 5 mg of donepezil HCl for a 4-week period, followed by 8 weeks of 10 mg of donepezil HCl. Cognitive, neurologic, functional, and behavioral assessments were conducted at baseline and at 4 and 12 weeks. Statistically significant improvement was observed in several cognitive domains including attention, memory, and executive functioning, as well as different aspects of behavior. These data suggest that donepezil HCl merits further study as a potentially viable treatment option for patients with cognitive impairment associated with MS.

Topics: Adult; Aged; Attention; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Middle Aged; Multiple Sclerosis; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Verbal Learning

In ambulatory anaesthesia the time required to recover from cognitive impairment should be as short as possible. The aim of this study was to compare the early cognitive recovery after remifentanil/propofol (R/P) and sevoflurane/fentanyl (S/F) anaesthesia.. Sixty patients scheduled for elective gynaecological laparoscopy and 24 female volunteers tested for the assessment of learning effects were investigated. After praemedication with midazolam anaesthesia was induced with propofol, atracurium and either 1 microgram/kg fentanyl or 1 microgram/kg remifentanil. For maintenance 0.25 microgram/kg/min remifentanil and 0.6 mg/kg/min propofol (R/P) or 1.7 vol% sevoflurane (S/F) were given. Both groups were ventilated with 30% oxygen in air and received metamizol for postoperative analgesia. Verbal Learning Test, Stroop Colour and Word Interference Test, Digit Symbol Substitution Test and Four Boxes Test were performed the day before surgery and 30 min, 1 h, 2 h and 4 h after termination of anaesthesia.. For remifentanil/propofol cognitive function was still impaired 2 h (Verbal Learning) and 4 h (Stroop, Digit Symbol Substitution and Four Boxes Test) after termination of anaesthesia. After sevoflurane/fentanyl anaesthesia cognitive impairment lasted the same duration in Four Boxes Test, but shorter in Stroop and Digit Symbol Substitution and could not be found in Verbal Learning Test.. The duration of cognitive impairment in the early postoperative period differed by the test procedures and the anaesthetic procedures used in this investigation. Recovery appeared to be faster after sevoflurane/fentanyl than after remifentanil/propofol at least in aspects of cognitive function.

Topics: Adult; Anesthesia, Inhalation; Anesthetics, Inhalation; Anesthetics, Intravenous; Cognition Disorders; Female; Fentanyl; Humans; Laparoscopy; Methyl Ethers; Neuropsychological Tests; Piperidines; Postoperative Complications; Propofol; Remifentanil; Sevoflurane

In several retrospective post-mortem studies, patients meeting clinical criteria for Alzheimer's disease (AD) who gained the greatest cognitive benefit from treatment with an acetylcholinesterase (AChE) inhibitor were found to have neocortical Lewy bodies accompanying classical AD neuropathology. This 'dementia with Lewy bodies' (DLB) subtype manifests both parkinsonian and psychopathologic features that set it apart from 'pure' AD (hereafter called AD). In the present preliminary study, 16 dementia patients were prospectively categorized as having DLB versus AD. Subjects were also categorized according to their profile on surface electromyographic (EMG) measures demonstrated in prior work to be analogues of clinically observed parkinsonian extrapyramidal signs (EPS). All patients were prescribed the AChE inhibitor donepezil (5 mg per day). At baseline and at 6 months, patients underwent cognitive testing with the Mini-Mental State Examination (MMSE) while caregivers assessed their psychopathologic status using the Behavioral Symptoms in Alzheimer's Disease (BEHAVE-AD) scale. The tester was blinded to the AD versus DLB classification of the patients. AD cases (N=12) had only a slight increase in cognitive scores, while DLB patients' (N=4) mean MMSE scores increased to a significantly greater degree. Furthermore, patients categorized by EMG as EPS positive (N=8) attained an increase in their mean MMSE score from baseline to 6 months that differed significantly from a decline in MMSE observed among their EPS negative (N=4) counterparts. For all subjects, an increase in MMSE scores across 6 months of treatment correlated with a decline in BEHAVE-AD scores.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Electromyography; Female; Humans; Indans; Lewy Body Disease; Male; Middle Aged; Motor Skills Disorders; Piperidines; Prospective Studies; Treatment Outcome

Regulatory guidelines in the US and Europe generally require that a drug specifically indicated for treating Alzheimer's disease (AD) must demonstrate an effect upon the core manifestations of dementia. Progressive cognitive and functional losses are the cardinal features of AD. In the US, current guidelines require that new AD treatments show effectiveness on performance-based measures of cognition and on clinician-rated global assessments. Improvement in function is also emphasized in the European guidelines. The primary instruments that have been used to evaluate changes in cognition and global function in most recent AD trials are the cognitive subscale of the Alzheimer's Disease Assessment Scale and a version of the Clinician's Interview Based Impression of Change, respectively. The results from three pivotal trials investigating the acetylcholinesterase inhibitor, donepezil, are used to demonstrate the way in which these tools are used, how to interpret the data they provide, and to determine their overall value in ascertaining efficacy in clinical practice.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Dose-Response Relationship, Drug; Guidelines as Topic; Humans; Indans; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Previously, studies using human neuroimaging and excitotoxic lesions in non-human primate have demonstrated an important role of ventrolateral prefrontal cortex (vlPFC) in higher order cognitive functions such as cognitive flexibility and the planning of behavioral sequences. In the present experiments, we tested effects on performance of temporary inactivation (using GABA receptor agonists) and dopamine (DA) D

Topics: Animals; Antipsychotic Agents; Baclofen; Callithrix; Cognition Disorders; Dopamine; Dopamine D2 Receptor Antagonists; Fluorobenzenes; GABA Agonists; gamma-Aminobutyric Acid; Goals; Memory, Short-Term; Muscimol; Piperidines; Prefrontal Cortex; Psychomotor Performance; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Spatial Behavior; Sulpiride

Aging-related cholinergic dysfunction, extensive neuroinflammation and oxidative stress in brain are predominant pathogenic factors for dementia. In the present study, we aimed to evaluate the protective effects of piperine, an alkaloid nutrient component of Piper nigrum, against cognitive impairment in a senescent mouse model induced by D-galactose (D-Gal) and to explore the underlying mechanisms. Senescent mouse model was established by repeated subcutaneous injection of D-Gal (150 mg/kg, once daily for 42 days). Fourteen days after the first D-Gal exposure, piperine (2.5, 5, 10 mg/kg) or vehicle was intraperitoneally administered once daily for 28 days. The cognitive function of mice was evaluated by Morris water maze test (MWM). Twenty-four hours after behavioral test, the cholinergic function and oxidative stress level in mouse hippocampus were measured by spectrophotometric assays. In addition, the hippocampal levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β and interleukin-6, were quantified using enzyme-linked immunosorbent assay. Expressions of glycogen synthase kinase-3β (GSK-3β) and its upstream or downstream molecules including phosphatidylinositol 3-kinase (PI3K)，protein kinase B (AKT), protein kinase C (PKC), NF-E2-related factor 2, nuclear factor-κB and microtubule-associated protein tau in hippocampus were determined by western blotting, immunohistochemical or immunofluorescent staining. Our data revealed that chronic D-Gal exposure in mice led to cognitive impairment in MWM, along with cholinergic malfunction, extensive oxidative stress and neuroinflammation, as well as hyperphosphorylation of tau protein in hippocampus. All these neurochemical, neuroinflammatory and cognitive alterations could be ameliorated by 4-week repeated piperine administration. Moreover, piperine also reversed D-Gal-induced GSK-3β activation through modulating PKC and PI3K/AKT pathways in senescent mouse hippocampus, suggesting GSK-3β-related signaling might be involved in the benefits of piperine against D-Gal-induced cognitive decline in mice.

Topics: Aging; Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Cellular Senescence; Cognition; Cognition Disorders; Cytokines; Galactose; Glutathione; Glycogen Synthase Kinase 3 beta; Hippocampus; Inflammation; Lipid Peroxidation; Male; Maze Learning; Mice; Models, Animal; Neurons; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Kinase C; Reactive Oxygen Species; Signal Transduction

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.

Topics: Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Cognition Disorders; Disease Models, Animal; Hippocampus; Inflammation; Infusions, Intraventricular; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Nitrogen; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Streptozocin

Piperine has been shown to have antioxidant activity and a cognitive-enhancing effect following long-term oral administration. In a comparative study of memantine, the current investigation threw light on the cognitive benefits of piperine. Lipid peroxidation and the ferric reducing antioxidant power (FRAP) of cerebrospinal fluid (CSF) and hippocampus in streptozotocin (STZ)-induced experimental dementia of the Alzheimer's type was measured. After reaching a criterion in a memory test, STZ-induced rats received piperine [2.5, 5, and 10mg/kg, intraperitoneally (i.p.)], vehicle, and memantine (10mg/kg, i.p.) for two weeks after the first STZ administration, or two weeks before and one week after, as a preventive approach. After the behavioral studies, samples were taken for biochemical and histological assays. An appropriate concentration of piperine (2.5mg/kg), on a daily basis, effectively increased the number of correct (non-repeated) arm entries and repressed reentry to a previously visited arm, in terms of reference errors as well as memantine (10mg/kg, i.p.), irrespective of the dose administered. The cognitive-enhancing effect induced by piperine at a relevant dose was simultaneous with CSF and hippocampal malonaldehyde decrement, and the redox balance was established to some extent by maintaining the FRAP levels of CSF near to those of the control. Similarly, the neuroprotective properties of piperine are in accordance with histopathological outcomes, which have shown an increased number of live cresyl violet (CV)-positive neurons in a dentate gyrus (DG) subregion. Therefore, the effects of piperine on the redox balance of CSF and hippocampal neurons may certainly contribute to the cognitive-enhancing activity of the drug.

Topics: Alkaloids; Analysis of Variance; Animals; Antibiotics, Antineoplastic; Avoidance Learning; Benzodioxoles; Cognition Disorders; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Hippocampus; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Memantine; Memory, Short-Term; Neurons; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Streptozocin

Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures. We studied the effect of a potent and selective irreversible MAGL inhibitor, CPD-4645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug's effects.. Diazepam-resistant SE was induced in adult mice fed with standard or ketogenic diet or in cannabinoid receptor type 1 (CB1) receptor knock-out mice. CPD-4645 (10 mg/kg, subcutaneously) or vehicle was dosed 1 and 7 h after status epilepticus onset in video-electroencephalography (EEG) recorded mice. At the end of SE, mice were examined in the novel object recognition test followed by neuronal cellloss analysis.. CPD-4645 maximal plasma and brain concentrations were attained 0.5 h postinjection (half-life = 3.7 h) and elevated brain 2-AG levels by approximately 4-fold. CPD-4645 administered to standard diet-fed mice progressively reduced spike frequency during 3 h postinjection, thereby shortening SE duration by 47%. The drug immediately abrogated SE in ketogenic diet-fed mice. CPD-4645 rescued neuronal cell loss and cognitive deficit and reduced interleukin (IL)-1β and cyclooxygenase 2 (COX-2) brain expression resulting from SE. The CPD-4645 effect on SE was similar in mice lacking CB1 receptors.. MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD-4645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation.

Topics: Animals; Brain; Brain Waves; Carbamates; Cognition Disorders; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistant Epilepsy; Electroencephalography; Excitatory Amino Acid Agonists; Fluoresceins; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoacylglycerol Lipases; Neurons; Piperidines; Random Allocation; Receptor, Cannabinoid, CB1; Recognition, Psychology; Status Epilepticus; Sulfonamides; Time Factors

The acetylcholinesterase inhibitor (AChEI) donepezil (DON) is recommended as a potential treatment for cognition after clinical traumatic brain injury (TBI) and therefore may be prescribed as an adjunct therapy during rehabilitation. However, a dose-response study evaluating DON after a controlled cortical impact (CCI) injury in rats did not reveal cognitive benefits.. The aim of this study was to determine the effect of DON on behavioral and histological outcome when combined with environmental enrichment (EE), a preclinical model of neurorehabilitation. It was hypothesized that the combined treatments would produce a synergistic effect yielding improved recovery over neurorehabilitation alone.. Isoflurane-anesthetized adult male rats received a CCI or sham injury and then were randomly assigned to EE or standard (STD) housing plus systemic injections of DON (0.25 mg/kg) or vehicle (VEH; 1.0 mL/kg saline) once daily for 19 days beginning 24 hr after injury. Function was assessed by established motor and cognitive tests on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 19.. DON was ineffective when administered alone. In contrast, EE conferred significant motor and cognitive benefits, and reduced cortical lesion volume vs. STD (p < 0.05). Combining the therapies weakened the efficacy of rehabilitation as revealed by diminished motor and cognitive recovery in the TBI+EE+DON group vs. the TBI+EE+VEH group (p < 0.05).. These data replicate previous findings showing that EE is beneficial and DON is ineffective after CCI and add to the literature a novel and unpredicted finding that supports neither the hypothesis nor the use of DON for TBI. Investigation of other AChEIs after CCI injury is necessary to gain further insight into the value of this therapeutic strategy.

Topics: Analysis of Variance; Animals; Brain Injuries, Traumatic; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Donepezil; Environment; Indans; Male; Maze Learning; Mental Disorders; Motor Activity; Neurologic Examination; Nootropic Agents; Piperidines; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Time Factors

Topics: Activating Transcription Factor 6; Animals; Carbamates; Cognition Disorders; Disease Models, Animal; Hippocampus; Humans; Huntington Disease; Kv Channel-Interacting Proteins; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Neuronal Calcium-Sensor Proteins; Neurons; Piperidines; Rotarod Performance Test

The clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses.. This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement.. Patients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog "no change" (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5-19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14-0.64).. ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement.. ISRCTN26167328.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Canada; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Double-Blind Method; Female; Galantamine; Goals; Humans; Indans; Male; Multicenter Studies as Topic; Outcome Assessment, Health Care; Piperidines; Severity of Illness Index

Topics: Acetaminophen; Aged; Aged, 80 and over; Automobile Driving; Cognition Disorders; Cognitive Dysfunction; Colonic Neoplasms; Delirium; Dementia; Donepezil; Early Detection of Cancer; Estrogen Replacement Therapy; Female; Geriatrics; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Oxycodone; Piperidines; Urinary Incontinence; Watchful Waiting

Subjects at risk of dementia benefit from participation in mentally stimulating activities, but no prior studies have investigated similar associations in Parkinson disease (PD). The aim of this study was to investigate the relationship between times spent engaging in mentally stimulating activities and cognitive functions in PD while accounting for the degree of primary neurodegenerations. PD patients (N = 41, 33 males; age 68.5 ± 7.2; Hoehn and Yahr stage 2.6 ± 0.6) completed the Community Health Activities Model Program for Seniors questionnaire, mini-mental state examination (MMSE), and [

Topics: Aged; Aged, 80 and over; Carbon Isotopes; Cognition Disorders; Cognitive Behavioral Therapy; Female; Humans; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Parkinson Disease; Phosphinic Acids; Piperidines; Positron-Emission Tomography; Regression Analysis; Tetrabenazine

Acetylcholinesterase (AChE) inhibitors are frequently prescribed to mitigate the cognitive decline in Alzheimer's disease. Thus, we investigated the possible efficacy of the AChE inhibitor 2-[(6-Nitro-2-benzothiazolyl)amino]-2-oxoethyl4-[2-(N,N-dimethylamino)ethyl] piperazine-1 carbodithioate (BPCT) in a streptozotocin (STZ)-induced Alzheimer's disease model (SADM).. First, we analyzed the molecular interaction of BPCT with AChE via a docking study. Then, the cognitive effects of BPCT (10 and 20mg/kg) were evaluated in intracerebroventricular STZ- and vehicle-administered rats with the elevated plus maze (EPM), Morris water maze (MWM), and active avoidance (AA) tests. Locomotor activity was also assessed.. Docking analysis indicated significant binding of BPCT to the AChE active site. In behavioral tests, STZ administration impaired cognitive performance in SADM rats versus control rats. Treatment with donepezil or BPCT significantly decreased the prolonged 2nd retention transfer latency and 2nd retention latency time values of the SADM group in the EPM and MWM tests, respectively. Further, prolonged latency times were decreased and reduced frequency of avoidance events were increased in the AA test. Locomotor activity between groups was not different.. BPCT appears to function as a central AChE inhibitor, and its improvement of deficits in SADM rats suggests that it has therapeutic potential in Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Avoidance Learning; Behavior, Animal; Benzothiazoles; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Indans; Locomotion; Maze Learning; Molecular Docking Simulation; Piperazines; Piperidines; Rats; Rats, Wistar; Streptozocin

Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT

Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Exploratory Behavior; Fluorobenzenes; Grooming; Male; Mice; Mice, Inbred Strains; Neostriatum; Piperidines; Prefrontal Cortex; Receptor, Serotonin, 5-HT2A; Reversal Learning; Serotonin 5-HT2 Receptor Antagonists; Stereotyped Behavior

Vascular endothelial dysfunction plays a key role in the pathogenesis of Alzheimer's disease (AD). Patients with AD have displayed decreased circulating endothelial progenitor cells (EPCs) which repair and maintain the endothelial function. Transplantation of EPCs has emerged as a promising approach for the management of cerebrovascular diseases including ischemic stroke, however, its impact on AD has been poorly described. Thus, the current study aimed at investigating the effects of bone marrow-derived (BM) EPCs transplantation in repeated scopolamine-induced cognitive impairment, an experimental model that replicates biomarkers of AD. Intravenously transplanted BM-EPCs migrated into the brain of rats and improved the learning and memory deficits. Meanwhile, they mitigated the deposition of amyloid plaques and associated histopathological alterations. At the molecular levels, BM-EPCs blunted the increase of hippocampal amyloid beta protein (Aβ), amyloid precursor protein (APP) and reinstated the Aβ-degrading neprilysin together with downregulation of p-tau and its upstream glycogen synthase kinase-3β (GSK-3β). They also corrected the perturbations of neurotransmitter levels including restoration of acetylcholine and associated esterase along with dopamine, GABA, and the neuroexitatory glutamate. Furthermore, BM-EPCs induced behavioral recovery via boosting of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and its upstream cAMP response element binding (CREB), suppression of the proinflammatory tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and upregulation of interleukin-10 (IL-10). BM-EPCs also augmented Nrf2 and seladin-1. Generally, these actions were analogous to those exerted by adipose tissue-derived mesenchymal stem cells (AT-MSCs) and the reference anti-Alzheimer donepezil. For the first time, these findings highlight the beneficial actions of BM-EPCs against the memory deficits and AD-like pathological dysfunction.

Topics: Adipose Tissue; Alzheimer Disease; Animals; Cell Movement; Cells, Cultured; Cognition Disorders; Cytokines; Disease Models, Animal; Donepezil; Endothelial Progenitor Cells; Gene Expression Profiling; Hippocampus; Indans; Intercellular Signaling Peptides and Proteins; Learning Disabilities; Male; Maze Learning; Mesenchymal Stem Cell Transplantation; Nerve Tissue Proteins; Neurotransmitter Agents; Piperidines; Random Allocation; Rats; Rats, Wistar; Scopolamine

Depression is a frequent comorbid condition in patients with Alzheimer's disease (AD). In the present study, we reported the effect of additional donepezil treatment for patients with geriatric depression who exhibited cognitive deficit and were diagnosed with AD during treatment for depression.. The present retrospective study investigated 14 AD outpatients who were diagnosed with geriatric depression at first and received antidepressant treatment. When apparent cognitive decline was observed, all of them were diagnosed with AD and received donepezil (5 mg/day) for at least 1 year. All patients underwent periodic examination of cognitive function (Mini-Mental State Examination, Rorschach Cognitive Index) and clinical evaluation (Clinical Dementia Rating). The 14 patients were classified into three groups according to their treatment course: (i) 'A' group, patients who showed cognitive impairment during a long course of treatment for depression; (ii) 'B' group, patients who showed cognitive impairment at an early stage of treatment for depression and started to take additional donepezil at least 20 months after the first examination; and (iii) 'C' group, patients who showed cognitive impairment at an early stage of treatment for depression and began taking additional donepezil within 10 months of the first examination. The clinical feature and treatment effects were examined for each group.. At 1 and 2 years after the start of treatment, the proportion of patients who had improved or maintained their Clinical Dementia Rating score was higher in 'A' and 'C' groups than in 'B' group. In 'B' group, additional donepezil treatment commenced later than in the other groups. Therefore, donepezil had an insufficient curative effect.. The results of this study suggested that early induction of donepezil treatment was necessary when apparent cognitive decline was identified during the treatment of geriatric depression.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Depression; Donepezil; Female; Geriatric Assessment; Humans; Indans; Male; Nootropic Agents; Piperidines; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Bromine; Cognition; Cognition Disorders; Cohort Studies; Drug Combinations; Excitatory Amino Acid Antagonists; Glutamates; Ketamine; Macaca; Magnesium; Male; Memory, Short-Term; Neuropsychological Tests; Phenethylamines; Piperidines; Psychomotor Performance; Pyridines; Reaction Time; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Space Perception

Inhibitors of cholinesterase are important drugs for therapy of Alzheimer's disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-quinuclidinyl benzilate (QNB, 2mgkg(-1)), administered intraperitoneally 1h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30min at the following dose rates; 1 (25.6mgkg(-1)), 2 (12.3mgkg(-1)), 3 (5.7mgkg(-1)), 4 (5.2mgkg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2mgkg(-1)) and donepezil (2.65mgkg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer's disease treatment is proposed.

Topics: Alzheimer Disease; Animals; Avoidance Learning; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Indans; Male; Maze Learning; Muscarinic Antagonists; Piperidines; Quinuclidinyl Benzilate; Rats, Wistar; Tacrine

Cognitive dysfunction is prevalent among brain tumor patients treated with radiotherapy (RT) and chemotherapy. However, there are no approved pharmacological interventions for cognitive dysfunction in cancer patients. The goal of this pilot study was to examine the efficacy of donepezil, an acetylcholinesterase inhibitor used to treat Alzheimer's disease, in improving cognitive functions in brain tumor patients previously treated with RT + chemotherapy or chemotherapy alone. Fifteen patients with a brain tumor received a single daily dose of donepezil for 24 weeks (5 mg for 4 weeks, then 10 mg for 20 weeks). Patients completed cognitive evaluations prior to initiating therapy (baseline), and about 12 weeks (mid-study) and 24 weeks (end-of-study) subsequent to initiation of donepezil therapy. The results of linear mixed models analysis, controlling for each patient's baseline cognitive test score, showed a significant post-baseline improvement in attention (WAIS-III digit span forward; p = 0.037), graphomotor speed (WAIS-III digit symbol; p = 0.035) and visual memory (BVMT-R-delay; p = 0.025). There was also an improvement in self-reported quality of life (FACT-Br, social well-being subscale; p = 0.01). The findings of this pilot study suggest that treatment with donepezil may improve some aspects of cognitive functions and quality of life in brain tumor patients. Similar findings were reported in two prior trials of donepezil in brain tumor survivors.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Neoplasm Staging; Neuropsychological Tests; Pilot Projects; Piperidines; Prognosis; Survival Rate; Survivors

The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer's disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Aß1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Aβ-injected mice, paralleling memory deficits. Starting from three days after Aβ injection, flavopiridol (0.5, 1 and 3mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1mg/kg) was able to rescue the loss of memory induced by Aβ1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antineoplastic Agents; Cognition Disorders; Cyclin-Dependent Kinases; Disease Models, Animal; Flavonoids; Frontal Lobe; Hippocampus; Male; Memory; Memory Disorders; Mice; Neurons; Peptide Fragments; Piperidines

Antagonism of the dopamine D3 receptor is considered a promising strategy for the treatment of cognitive impairment associated with schizophrenia. We have previously reported that the atypical antipsychotic blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptor antagonist, highly occupies dopamine D3 receptors at its antipsychotic dose range in rats. In the present study, we evaluated the effects of blonanserin on executive function in common marmosets using the object retrieval with detour (ORD) task. The dopamine D3 receptor-preferring agonist (+)-PD-128907 at 1mg/kg decreased success rate in the difficult trial, but not in the easy trial. Since the difference between the two trials is only cognitive demand, our findings indicate that excess activation of dopamine D3 receptors impairs executive function in common marmosets. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by (+)-PD-128907 in the difficult trial. This finding indicates that blonanserin has beneficial effect on executive function deficit induced by activation of the dopamine D3 receptor in common marmosets. Next, and based on the glutamatergic hypothesis of schizophrenia, the common marmosets were treated with the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. Ketamine at sub-anesthetic doses decreased success rate in the difficult trial, but not in the easy trial. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by ketamine in the difficult trial. The findings of this study suggest that blonanserin might have beneficial effect on executive dysfunction in patients with schizophrenia.

Topics: Animals; Antipsychotic Agents; Benzopyrans; Callithrix; Cognition Disorders; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Executive Function; Female; Ketamine; Male; Mental Recall; Oxazines; Piperazines; Piperidines

Sunitinib, a tyrosine kinase inhibitor, is clinically used for the treatment of cancer. In this study, we found for the first time that sunitinib inhibits acetylcholinesterase (AChE) at submicromolar concentrations in vitro. In addition, sunitinib dramatically decreased the hippocampal and cortical activity of AChE in a time-dependent manner in mice. Molecular docking analysis further demonstrates that sunitinib might interact with both the catalytic anion and peripheral anionic sites within AChE, which is in accordance with enzymatic activity results showing that sunitinib inhibits AChE in a mixed pattern. Most importantly, we evaluated the effects of sunitinib on scopolamine-induced cognitive impairments in mice by using novel object recognition and Morris water maze tests. Surprisingly, sunitinib could attenuate cognitive impairments to a similar extent as donepezil, a marketed AChE inhibitor used for the treatment of Alzheimer's disease. In summary, our results have shown that sunitinib could potently inhibit AChE and attenuate cognitive impairments in mice.

Topics: Acetylcholinesterase; Animals; Antineoplastic Agents; Cholinergic Antagonists; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Exploratory Behavior; Indans; Indoles; Male; Maze Learning; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Piperidines; Pyrroles; Scopolamine; Sunitinib

Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases-enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments-probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission.

Topics: Animals; Behavior, Animal; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Ethanol; Indans; Male; Maze Learning; Memory Disorders; Motor Activity; Nootropic Agents; Piperidines; Rats, Wistar; Reaction Time; Rivastigmine; Rotarod Performance Test; Spatial Memory; Time Factors

People with special needs undergoing dental surgery frequently require general anesthesia. We investigated the effect of remifentanil vs fentanyl on stress response and postoperative pain in people with special needs undergoing day-case dental surgery.. Forty-six adult patients with cognitive impairment undergoing day-case dental surgery under general anesthesia were allocated to receive intraoperatively either fentanyl 50 μg iv bolus (group F, n = 23) or continuous infusion of remifentanil 0.5-1 μg/kg/min (group R, n = 23). Iintraoperative hemodynamic parameters were recorded and serum inflammatory mediators [tumor necrosis factor-α, substance-P], stress hormons (melatonin, cortisol) and β-endorphin were measured. Postoperative pain was assessed during the first postoperative 12 hours with the Wong-Baker faces pain-rating scale.. Demographics were similar in two groups. The two groups did not differ regarding their effects on inflammatory mediators, stress hormons and postoperative pain scores. However, the use of remifentanil prevented intraoperative increases of arterial blood pressure and heart rate.. Remifentanil and fentanyl did not affect differently stress and inflammatory hormones during day-case dental surgery, although remifentanil may render intraoperative management of hemodynamic responses easier. Both opioids are equally efficient for postoperative pain management following dental surgery in people with special needs.

Topics: Adult; Ambulatory Surgical Procedures; Analgesics, Opioid; Cognition Disorders; Female; Fentanyl; Hemodynamics; Humans; Male; Pain, Postoperative; Pilot Projects; Piperidines; Remifentanil; Stress, Psychological

Topics: Aging; Anesthesia, General; Anesthesiology; Anesthetics; Brain; Cholinergic Neurons; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Infusions, Intravenous; Learning; Memory; Physostigmine; Piperidines; Postoperative Period; Quality of Life; Time Factors

A considerable number of patients with breast cancer complain of cognitive impairment after chemotherapy. In this study, we showed that donepezil enhanced memory function and increased brain glucose metabolism in a rat model of cognitive impairment after chemotherapy using behavioral analysis and positron emission tomography (PET). We found that chemotherapy affected spatial learning ability, reference memory, and working memory and that donepezil improved these cognitive impairments. According to PET analysis, chemotherapy reduced glucose metabolism in the medial prefrontal cortex and hippocampus, and donepezil increased glucose metabolism in the bilateral frontal lobe, parietal lobe, and hippocampus. Reduced glucose metabolism was more prominent after treatment with doxorubicin than cyclophosphamide. Our results demonstrated the neural mechanisms for cognitive impairment after chemotherapy and show that cognition was improved after donepezil intervention using both behavioral and imaging methods. Our results suggested that donepezil can be employed clinically for the treatment of cognitive deficits after chemotherapy.

Topics: Animals; Antineoplastic Agents; Brain; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Female; Fluorodeoxyglucose F18; Indans; Maze Learning; Memory; Piperidines; Positron-Emission Tomography; Rats, Sprague-Dawley

Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan catabolism, was recently established as one of the potential players involved in the pathogenesis of Alzheimer's disease (AD). Coptisine is a main pharmacological active constituent of the traditional Chinese medicinal prescription Oren-gedoku-to (OGT) which has therapeutic potential for the treatment of AD. Our recent studies have demonstrated that OGT significantly inhibited recombinant human IDO activity, which shed light on the possible mechanism of OGT's action on AD. Here, we characterized the effects of coptisine in an AD mouse model on the basis of its IDO inhibitory ability. Coptisine was found to be an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 μM and an IC50 value of 6.3 μM. In AβPP/PS1 transgenic mice, oral administration of coptisine inhibited IDO in the blood and decreased the activation of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-β peptide 1-42 and interferon-γ showed reduction of cell viability and enhancement of IDO activity, while coptisine treatment increased cell viability based on its reversal effect on the enhanced activity of IDO. In conclusion, our present findings provide further evidence supporting the critical links between IDO, KP, and AD, and demonstrate coptisine, a novel IDO inhibitor, as a potential new class of drugs for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Berberine; Brain; Cell Survival; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Enzyme Inhibitors; Humans; Indans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Male; Mice, Transgenic; Nootropic Agents; PC12 Cells; Piperidines; Plaque, Amyloid; Presenilin-1; Rats

Topics: Analgesia; Analgesics, Opioid; Cognition Disorders; Electroencephalography; Humans; Male; Nerve Net; Piperidines; Remifentanil

Cognitive deficits in patients with Alzheimer's disease, Parkinson's disease, traumatic brain injury and stroke often involve alterations in cholinergic signalling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory.. Scopolamine-induced memory impairment provides a rapid and reversible phenotypic screening paradigm for cognition enhancement drug discovery. Male C57BL/6J mice given scopolamine (1 mg·kg(-1) ) were used to evaluate the ability of LS-1-137, a novel sigma (σ1) receptor-selective agonist, to improve the cognitive deficits associated with muscarinic antagonist administration.. LS-1-137 is a high-affinity (Ki = 3.2 nM) σ1 receptor agonist that is 80-fold selective for σ1, compared with σ2 receptors. LS-1-137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1-137 was found to partially reverse the learning deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1-137 treatment was also found to trigger the release of brain-derived neurotrophic factor from rat astrocytes.. The σ1 receptor-selective compound LS-1-137 may represent a novel candidate cognitive enhancer for the treatment of muscarinic receptor-dependent cognitive deficits.

Topics: Acetanilides; Animals; Astrocytes; Avoidance Learning; Brain-Derived Neurotrophic Factor; Cognition Disorders; Ligands; Male; Maze Learning; Mice; Muscarinic Antagonists; Piperidines; Rats; Receptors, sigma; Scopolamine; Sigma-1 Receptor

Topics: Brain Neoplasms; Cognition Disorders; Female; Humans; Indans; Male; Piperidines

The relationship between medial temporal lobe atrophy (MTA) and cognitive impairment in patients with dementia with Lewy bodies (DLB) remains unclear. We examined this relationship using voxel-based specific regional analysis system for Alzheimer disease (VSRAD) advance software, which allowed us to quantify the degree of MTA on images obtained from magnetic resonance imaging (MRI) scans.. Thirty-seven patients diagnosed with DLB were recruited and scanned with a 1.5 Tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z-score (Z score) on the target VOI, with higher scores indicating more severe MTA. Mini-Mental State Examination (MMSE) and the Revised Hasegawa Dementia Scale (HDS-R), which strengthened the measures of memory and language more than MMSE, were used to assess the presence of cognitive impairment.. A negative correlation was found between the Z score and MMSE total scores or the HDS-R total scores. A stepwise multiple regression analysis performed to adjust the covariate effects of sex, age, the onset age of the disease, duration of DLB, years of education, and donepezil treatment showed that the HDS-R total scores were independently associated with the Z score, whereas MMSE total scores were not.. These results suggest that MTA is related to cognitive impairment in patients with DLB, particularly the regions of orientation, immediate and delayed recall, and word fluency.

Topics: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Atrophy; Cognition Disorders; Donepezil; Entorhinal Cortex; Female; Hippocampus; Humans; Indans; Language; Lewy Body Disease; Magnetic Resonance Imaging; Male; Mental Recall; Neuropsychological Tests; Nootropic Agents; Piperidines; Software; Temporal Lobe; Verbal Behavior

Phloretin (PHL), a dihydrochalcone flavonoid usually present in the roots and leaves of apple tree. In vitro study on GT1-7 immortalized hypothalamic neurons exposed to amyloid beta (25-35), demonstrated that PHL significantly influenced membrane fluidity and potential. PHL also significantly decreased excitotoxicity by restoring the calcium homeostasis in the same. Thus, PHL proves to be a promising therapeutic moiety which should be further screened in the treatment of Alzheimer's disease. The objective of the present study was to evaluate the nootropic, neuroprotective and neurotrophic roles of PHL in the subacute scopolamine induced amnesia in mice. In this study, mice were pretreated with PHL 2.5mg/kg, 5mg/kg, 10mg/kg and Donepezil (DON) 1mg/kg intraperitoneally (i.p) for 14days. The last 7days of treatment regimen included daily injection of SCP 1.5mg/kg to induce cognitive deficits. Mice were subjected to behavioral analysis. Biochemical estimation of the brain homogenates for acetylcholinesterase and oxidative stress biomarkers were conducted. Furthermore, immunohistochemical analysis for the brain derived neurotrophic factor (BDNF) was carried out particularly in the hippocampus. PHL was found to significantly improve the performance of mice in Morris water maze test (P<0.001) and significantly decreased the acetylcholinesterase activity (P<0.001) at all doses compared to SCP treated mice. Also, PHL significantly elevated the activity of antioxidant enzymes viz. superoxide dismutase, catalase, reduced glutathione levels (P<0.001) and decreased malonaldehyde levels (P<0.001) in comparison with the SCP group. Immunohistochemistry revealed that PHL treatment dose dependently improved BDNF levels in the hippocampus which were found to be significantly depleted (P<0.001) in the SCP group. Additionally, PHL (10mg/kg) significantly enhanced the spatial memory formation (P<0.05) and neurotrophicity (P<0.001) compared to DON (1mg/kg). The aforementioned research findings suggested that PHL has nootropic, neuroprotective and neurotrophic activities in SCP induced memory impaired mice and hence, is a promising therapeutic moiety in the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amnesia; Animals; Antioxidants; Brain-Derived Neurotrophic Factor; Cognition Disorders; Donepezil; Glial Fibrillary Acidic Protein; Indans; Male; Maze Learning; Mice; Motor Activity; Muscarinic Agonists; Neuroprotective Agents; Nootropic Agents; Phloretin; Piperidines; Scopolamine

Topics: Analgesia; Analgesics, Opioid; Cognition Disorders; Electroencephalography; Humans; Male; Nerve Net; Piperidines

Topics: Analgesia; Analgesics, Opioid; Cognition Disorders; Electroencephalography; Humans; Male; Nerve Net; Piperidines

Topics: Brain Neoplasms; Cognition Disorders; Female; Humans; Indans; Male; Piperidines

Topics: Brain Neoplasms; Cognition Disorders; Female; Humans; Indans; Male; Piperidines

Topics: Animals; Cholinesterase Inhibitors; Cognition Disorders; Discrimination, Psychological; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Exploratory Behavior; Hyperlipoproteinemia Type II; Indans; Learning; Memory; Mice, Inbred C57BL; Mice, Knockout; Nootropic Agents; Piperidines; Psychological Tests; Receptors, LDL; Space Perception

Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.

Topics: Acetylcholine; Animals; Autistic Disorder; Caudate Nucleus; Cholinesterase Inhibitors; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Donepezil; Drug Administration Routes; Exploratory Behavior; Indans; Interpersonal Relations; Locomotion; Male; Maze Learning; Mice; Mice, Inbred Strains; Piperidines; Social Behavior Disorders; Stereotyped Behavior

p3-Alcα is a metabolic fragment of Alcadeinα (Alcα). Similar to the generation of the p3 fragment from amyloid-β protein precursor (AβPP) processing, Alcα is cleaved by α- and γ-secretases, leading to the secretion of p3-Alcα peptides into cerebrospinal fluid (CSF). p3-Alcα is also detected in the plasma, similar to amyloid-β (Aβ), which is a metabolic fragment of AβPP cleaved by amyloidogenic β- and γ-secretases. Because p3-Alcα is a non-aggregatable and stable peptide, unlike aggregatable Aβ and metabolically labile p3 of AβPP, the changes of p3-Alcα in quality and/or quantity in CSF and plasma are expected to be a marker for assessing alteration of substrate cleavage by γ-secretase, such as Aβ generation from AβPP. The present study describes a sandwich enzyme-linked immunosorbent assay for quantifying levels of p3-Alcα35, the major form of the p3-Alcα species, and examines levels of p3-Alcα35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alcα35 levels were significantly increased with a concomitant decrease in the Mini-Mental State Examination score, or in clinically diagnosed Alzheimer's disease (AD) patients, when compared with age-matched non-demented subjects. The values were significantly lower in AD subjects who were administered donepezil, when compared to AD subjects without donepezil treatment. The increase in plasma p3-Alcα35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a γ-secretase malfunction, or a disorder of the clearance of peptides.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid Precursor Protein Secretases; Biomarkers; Calcium-Binding Proteins; Cognition Disorders; Cohort Studies; Disease Progression; Donepezil; Endophenotypes; Female; Humans; Indans; Male; Nootropic Agents; Peptide Fragments; Piperidines

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Drug Inverse Agonism; Half-Life; Haplorhini; Memory, Short-Term; Nootropic Agents; Piperidines; Pyridazines; Rats; Receptors, Histamine H3; Stereoisomerism; Structure-Activity Relationship

Although several case reports suggested that donepezil hydrochloride can induce bradycardia or atrioventricular block, the details remain unclear. We implemented a study of the impact of donepezil hydrochloride administration on PR, RR, and QT intervals.. The subjects were 18 patients who were diagnosed with either dementia or cognitive disorder (DSM-IV-TR) and were hospitalized between January 2011 and December 2012. After hospitalization, they were treated with donepezil hydrochloride. Clinical parameters and electrocardiograms before and after the administration of donepezil hydrochloride were retrieved from the patients' medical records.. After the administration of donepezil hydrochloride, the mean PR interval significantly increased from 177.3 ± 30.9 to 186.8 ± 38.4 ms (p<0.001). And the mean RR interval also significantly increased from 850.3 ± 112.5 to 886.7 ± 136.4 ms (p=0.014). The mean difference in the PR interval before and after the administration of donepezil hydrochloride was 9.5 ± 17.1 (range=-21.0-44.0) ms. The QT intervals were unaffected by the administration of donepezil hydrochloride.. Care should be taken when administering donepezil to patients with atrioventricular block, or patients taking other drugs that can prolong the PR interval. Copyright © 2014 John Wiley & Sons, Ltd.

Topics: Aged; Cognition Disorders; Dementia; Donepezil; Electrocardiography; Female; Heart; Humans; Indans; Male; Nootropic Agents; Piperidines

Cognitive impairment associated with schizophrenia (CIAS) is an important etiological feature of this disorder with implications for symptom severity and quality of life. Acute N-methyl-d-aspartate receptor (NMDAR) blockade using MK-801, a non-competitive antagonist to NMDARs, is assumed to produce temporary cognitive impairments in mice similar to those seen in schizophrenia patients. Less is known, however, about the effects of subchronic MK-801 administration on cognition. In the current study, twenty-eight male C57/BL6 mice received a daily dose of MK-801 (0.1mg/kg, i.p.) for seven days. Spatial memory was assessed using an object location task prior to MK-801 administration as well as at multiple time points after the treatment. Subchronic treatment with MK-801 caused lasting memory deficits, which were ameliorated by acute doses of an acetylcholinesterase inhibitor (donepezil) and an alpha-7 nicotinic agonist (PHA 568487), but were unaffected by acute administration of the atypical antipsychotic risperidone. Subchronic administration of MK-801 may lend this pharmaceutical model increased face validity, while its resemblance to prodromal schizophrenia makes it suitable for screening new CIAS treatments.

Topics: Acetylcholinesterase; alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Aza Compounds; Cholinesterase Inhibitors; Cognition Disorders; Dioxins; Disease Models, Animal; Dizocilpine Maleate; Donepezil; Indans; Male; Mice, Inbred C57BL; Nicotinic Agonists; Nootropic Agents; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Spatial Memory

There is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.. To investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.. Cross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [(11)C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [(11)C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.. There were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (-0.98 ± 1.01) compared to the non-diabetics (-0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).. Diabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.

Topics: Aged; Butyrates; Carbon Isotopes; Cognition Disorders; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Parkinson Disease; Piperidines; Positron-Emission Tomography; Severity of Illness Index; Tetrabenazine

Cognitive impairment and dementia treatment costs are significant for health systems. According to national and international guidelines, recommended drugs for treatment of dementias are cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. Despite these guidelines recommendations, other nootropics, vasodilators and antioxidants are often used in Argentina. The purpose of this study was to describe and compare the prescription pattern of commonly used drugs for the treatment of cognitive disorders and dementia in different regions of Argentina. An observational, retrospective study of 1814108 recipes prescribed to National Institute of Social Services for Retired and Pensioners outpatients during the during the second half of 2008 and the first and second half of 2009 was performed, taking in count the whole country and also different Argentina's regions. Demographic variables, quantity and rate of prescriptions, dosage forms and strengths were analyzed. Considering the entire country, memantine was the most prescribed drug in these periods (570893 packages). An increase in the memantine, donepezil, rivastigmine and idebenone rates of prescription was observed. Prescription rate of memantine increased in the North-West and North-East regions, that of idebenone in the North-East region and Patagonia and donepezil in the North-East region. Non recommended drugs were highly prescribed in all the analyzed regions. Some of them were indicated to young and middle-aged patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Argentina; Child; Child, Preschool; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Dementia, Vascular; Donepezil; Drug Prescriptions; Female; Galantamine; Humans; Indans; Infant; Male; Memantine; Middle Aged; Phenylcarbamates; Piperidines; Retrospective Studies; Rivastigmine; Young Adult

Altered cognitive function is a common feature of both the early and later stages of Parkinson's disease (PD) that involves alterations in cortical dopamine content. Adenosine A2A antagonists, such as istradefylline, improve motor function in PD, but their effect on cognitive impairment has not been determined.. The present study investigated whether impairment of working memory due to the loss of dopaminergic input into the prefrontal cortex (PFC) is reversed by administration of istradefylline. We also evaluated whether A2A antagonist administration modulates dopamine levels in the PFC.. Bilateral lesions of the dopaminergic input to the PFC were produced in rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using an object recognition task and delayed alternation task. The effects of istradefylline, donepezil and methamphetamine on cognitive performance were examined. In addition, the effect of istradefylline on extracellular dopamine levels in the PFC was studied.. PFC dopamine levels and cognitive performance were significantly reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine improved cognitive performance of PFC-lesioned rats. Istradefylline increased dopamine levels in the PFC in both normal and PFC-lesioned rats.. PFC dopaminergic input plays an important role in working memory performance. Blockade of A2A receptors using istradefylline reverses the changes in cognitive function, and this may be due to an increase in PFC dopamine content. Adenosine A2A receptor antagonists not only improve motor performance in PD but may also lead to improved cognition.

Topics: Adenosine A2 Receptor Antagonists; Animals; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Dopamine; Indans; Male; Memory Disorders; Memory, Short-Term; Methamphetamine; Oxidopamine; Piperidines; Prefrontal Cortex; Purines; Rats; Rats, Sprague-Dawley

Acetylcholinesterase inhibitors (AChEIs) are approved to treat the symptoms of mild to moderate Alzheimer's disease by restoring acetylcholine levels at synapses where the neurotransmitter has been depleted due to neurodegeneration. This assumption is challenged by more recent clinical studies suggesting the potential for disease-modifying effects of AChEIs as well as in vitro studies showing neuroprotective effects. However, few preclinical studies have assessed whether the improvement of cognitive symptoms may be mediated by reductions in Abeta or Tau pathology.. The objective of the present study was to determine whether short-duration treatment with donepezil could improve spatial learning and memory in transgenic mice overexpressing mutant human amyloid precursor protein (hAPP) and presenilin 1 (PS1) (Dewachter et al., J Neurosci 20(17):6452-6458, 2000) after amyloid pathology has fully developed, consistent with early stages of Alzheimer'sdisease in humans. In parallel, the effect of donepezil treatment on brain amyloid, Tau, and glial endpoints was measured.. This study showed a significant improvement in reference memory in hAPP/PS1 mice along with dose-dependent reductions in brain amyloid-β (Aβ).. These results suggest that the observed cognitive improvement produced by donepezil in Alzheimer's disease may be due, at least in part, to reduction of brain Aβ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Piperidines; Presenilin-1; Synapses

The cognitive deficits associated with schizophrenia are recognized as a core component of the disorder, yet there remain no available therapeutics to treat these symptoms of the disease. As a result, there is a need for establishing predictive preclinical models to identify the therapeutic potential of novel compounds. In the present study, rhesus monkeys were trained in the object retrieval-detour task, which is dependent on the prefrontal cortex, a brain region implicated in the cognitive deficits associated with schizophrenia. The NMDA receptor antagonist ketamine significantly impaired performance without affecting measures of motor or visuospatial abilities. Pre-treatment with the nicotinic α7 agonist GTS-21 (0.03 mg/kg) significantly attenuated the ketamine-induced impairment, consistent with reports from clinical trials suggesting that nicotinic α7 receptor agonism has pro-cognitive potential in clinical populations. In contrast, pretreatment with the acetylcholinesterase inhibitor donepezil failed to reverse the ketamine-induced impairment, consistent with studies showing a lack of pro-cognitive effects in patients with schizophrenia. These data suggest that the ketamine-impaired object retrieval-detour task could provide a model with improved predictive validity for drug development, and confirm the need for additional efforts in back-translation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Benzylidene Compounds; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Indans; Ketamine; Macaca mulatta; Male; Molecular Targeted Therapy; Nicotinic Agonists; Nootropic Agents; Piperidines; Psychomotor Performance; Pyridines; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Schizophrenia

Autism is a neurodevelopmental disorder in which the first diagnostic symptom is unusual reciprocal social interactions. Approximately half of the children diagnosed with an autism spectrum disorder also have intellectual impairments. General cognitive abilities may be fundamental to many aspects of social cognition. Cognitive enhancers could conceivably be of significant benefit to children and adults with autism. AMPAKINE compounds are a novel class of pharmacological agents that act as positive modulators of AMPA receptors to enhance excitatory glutamatergic neurotransmission. This class of compounds was reported to improve learning and memory in several rodent and non-human primate tasks, and to normalize respiratory abnormalities in a mouse model of Rett syndrome. Here we evaluate the actions of AMPA compounds in adult male and female BTBR mice, a well characterized mouse model of autism. Acute treatment with CX1837 and CX1739 reversed the deficit in sociability in BTBR mice on the most sensitive parameter, time spent sniffing a novel mouse as compared to time spent sniffing a novel object. The less sensitive parameter, time in the chamber containing the novel mouse versus time in the chamber containing the novel object, was not rescued by CX1837 or CX1739 treatment. Preliminary data with CX546, in which β-cyclodextrin was the vehicle, revealed behavioral effects of the acute intraperitoneal and oral administration of vehicle alone. To circumvent the artifacts introduced by the vehicle administration, we employed a novel treatment regimen using pellets of peanut butter for drug delivery. Absence of vehicle treatment effects when CX1837 and CX1739 were given in the peanut butter pellets, to multiple cohorts of BTBR and B6 control mice, confirmed that the pharmacologically-induced improvements in sociability in BTBR were not confounded by the administration procedures. The highest dose of CX1837 improved the cognitive deficit in novel object recognition in BTBR. No drug effects were detected on the high levels of repetitive self-grooming in BTBR. In open field tests, CX1837 and CX1739 did not induce hyperactivity or sedation in either strain. It is interesting to speculate that the ability of CX1837 and CX1739 to restore aspects of sociability in BTBR mice could utilize synaptic mechanisms regulating social cognition, suggesting a potential pharmacological target for interventions to treat symptoms of autism. This article is part of a Special Issue ent

Topics: Animals; Autistic Disorder; Behavior, Animal; Cognition Disorders; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Investigational; Excitatory Amino Acid Agonists; Female; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Molecular Targeted Therapy; Nootropic Agents; Piperidines; Random Allocation; Receptors, AMPA; Recognition, Psychology; Social Behavior; Social Behavior Disorders

Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic α(1), α(2c), 5-HT(2A) 5-HT₇, moderate affinity for adrenergic α(2a) and D₂ receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT₇ receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antipsychotic Agents; Behavior, Animal; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Investigational; Male; Memory, Short-Term; Mice; Mice, Inbred Strains; Nootropic Agents; Piperidines; Pyridazines; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists

The current standards of care for Alzheimer's disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of muscarinic and nicotinic receptors. The M1 muscarinic receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects.. Here we investigated whether the selective M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow.. PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies.. These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer's disease.

Topics: Allosteric Regulation; Alzheimer Disease; Animals; Brain; Cognition; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Macaca fascicularis; Macaca mulatta; Male; Mice; Piperidines; Quinolizines; Rats; Rats, Wistar; Receptor, Muscarinic M1; Regional Blood Flow; Scopolamine; Species Specificity

Approximately 50% of patients who survived after aneurysmal subarachnoid hemorrhage (SAH) have cognitive or neurobehavioral dysfunction. The mechanisms are not known. NR2B, one of the subunits of N-methyl-d-aspartate (NMDA) receptors, has been proved to be an important factor for synapse function and behavior cognition. Experiment 1 aimed to investigate the timecourse of the NR2B expression in the cortex, hippocampus, and cerebellum after SAH in rats. In experiment 2, we assessed the effect of Ro 25-6981 (a specific NR2B antagonist) on regulation of learning deficits and behavioral activity following SAH. All SAH animals were subjected to injection of autologous blood into the prechiasmatic cistern once on day 0. NR2B was assessed by Western blot analysis and immunohistochemistry. Cognitive and memory changes were investigated in the Morris water maze. As a result, the expression of NR2B was decreased remarkably in SAH groups compared with the control group and the low ebb was on days 1-3. The immunohistochemical staining demonstrated expression of NR2B was present mainly in the neurons in all of the three different regions, such as the cortex, hippocampus, and cerebellum. After Ro 25-6981 intraperitoneal administration, learning deficits induced by SAH was markedly aggravated and clinical behavior scale was also significantly decreased. Our results suggest that NR2B expression is down-regulated in the brain after experimental SAH and NR2B antagonism resulted in augmentation of the development of cognitive dysfunction after SAH.

Topics: Animals; Behavior, Animal; Cerebellum; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Down-Regulation; Hippocampus; Maze Learning; Neurons; Phenols; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Subarachnoid Hemorrhage

Given that amyloid-β 42 (Aβ42) is believed to be a culprit in Alzheimer's disease (AD), reducing Aβ42 production should be a potential therapeutic approach. γ-Secretase modulators (GSMs) cause selective reduction of Aβ42 or both reduction of Aβ42 and Aβ40 without affecting total Aβ through shifting the γ-cleavage position in amyloid precursor protein. We recently reported on GSM-2, one of the second-generation GSMs, that selectively reduced brain Aβ42 level and significantly ameliorated cognitive deficits in plaque-free 5.5-month-old Tg2576 AD model mice. Here, we investigated the effects of GSM-2 on 10-, 14-, and 18-month-old mice which had age-dependent increase in amyloid plaques. Eight-day treatment with GSM-2 significantly ameliorated cognitive deficits measured by Y-maze task in the mice of any age. However, GSM-2 reduced brain soluble Aβ42 only in 10-month-old mice. In contrast, GSM-2 markedly reduced newly synthesized soluble Aβ42 in both 10- and 18-month-old mice with similar efficacy when measured using the stable isotope-labeling technique, suggesting that nascent Aβ42 plays a more significant role than plaque-associated soluble Aβ42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing Aβ42 synthesis in AD therapeutic regimens.

Topics: Acetates; Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Antibodies; Chromatography, Liquid; Cognition Disorders; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Hippocampus; Humans; Mass Spectrometry; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Piperidines

Diagnosing and treating patients with Alzheimer's disease (AD) at an early stage should improve the quality of life of the patient and caregiver. In the United Kingdom, cost-effectiveness of early assessment of individuals presenting with subjective memory complaints and treating those with AD with donepezil was evaluated.. A discrete event simulation of AD progression and the effect of treatment interventions was developed. Patient-level data from donepezil trials and a 7-year follow-up registry were used to model correlated longitudinal rates of change in cognition, behavior, and function. Other epidemiological and health services data, including estimates of undiagnosed dementia and delays in diagnosis, were based on published sources. Simulated individuals were followed up for 10 years.. In the base-case estimates, 17 patients need to be assessed to diagnose one patient with AD, resulting in an average assessment cost of £4100 ($6000; $1 US = £0.68 UK) per patient diagnosed (2007 cost year). In comparison with a scenario without early assessment or pharmacologic treatment, early assessment reduces health care costs by £3600 ($5300) per patient and societal costs by £7750 ($11,400). Savings are also substantial compared with treatment without early assessment, averaging £2100 ($3100) in health care costs, and £5700 ($8400) in societal costs. Results are most sensitive to estimates of patient care costs and the probability of patients reporting subjective memory complaints. In probabilistic sensitivity analysis, early assessment leads to savings or is highly cost-effective in the majority of cases.. Although early assessment has significant up-front costs, identifying AD patients at an early stage results in cost savings and health benefits compared with no treatment or treatment in the absence of early assessment.

Topics: Alzheimer Disease; Caregivers; Cognition Disorders; Cost-Benefit Analysis; Disease Progression; Donepezil; Female; Health Care Costs; Humans; Indans; Longitudinal Studies; Male; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Quality of Life; Statistics as Topic; United Kingdom

Multiple sclerosis (MS) is the leading cause of neurological disability among young and middle-aged adults. One of the most devastating consequences of MS in this relatively young population group is unemployment. Although certain demographic and disease factors have been associated with employment, few studies have examined the contribution of person-specific factors, such as personality.. The goal of this study was to determine the extent to which personality, demographics, and clinical measures contribute to unemployment in MS.. A total of 101 individuals with MS who were enrolled in a clinical trial on cognition underwent a brief neuropsychological battery and completed questionnaires related to vocation, mood, fatigue, and personality. Neurological impairment was measured with the Expanded Disability Status Scale (EDSS).. Employment status was related with disease duration, MS subtype, level of neurological impairment, fatigue, performance on measures assessing information processing speed (Symbol Digit Modalities Test (SDMT)), learning and memory (Selective Reminding Test), and the personality characteristic of persistence. Based on a forward logistic regression analysis, EDSS, SDMT, and persistence were the strongest predictors of employment status.. These findings underscore the importance of personality on outcomes in MS and point to the need for more clinical attention and research in this area.

Topics: Adult; Affect; Chi-Square Distribution; Cognition; Cognition Disorders; Cost of Illness; Cross-Sectional Studies; Disability Evaluation; Donepezil; Fatigue; Female; Humans; Indans; Learning; Logistic Models; Male; Memory; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; New York; Nootropic Agents; Personality; Piperidines; Predictive Value of Tests; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Unemployment

Cognitive dysfunction affects approximately half of the patients with multiple sclerosis (MS). Cholinesterase inhibitor drugs are approved to treat cognitive dysfunction associated with degenerative dementia.. To critically assess current evidence regarding the efficacy of the cholinesterase inhibitor, donepezil in the treatment of MS-associated cognitive impairment.. The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of behavioral neurology and MS.. A randomized control trial was selected for critical appraisal. This trial randomized MS patients to receive donepezil 10 mg daily or placebo for treatment of MS-related cognitive dysfunction. There was no significant treatment effect found between the 2 groups on either the primary outcome of memory or any of the secondary cognitive measures. Post hoc analyses suggested a trend favoring donepezil in subjects with greater baseline cognitive dysfunction.. Donepezil 10 mg daily for 24 weeks is not superior to placebo in improving MS-related cognitive dysfunction.

Topics: Cognition Disorders; Donepezil; Humans; Indans; Memory; Multiple Sclerosis; Nootropic Agents; Piperidines; Treatment Outcome

Neurocognitive deficits are a recognized late effect of curative brain tumor therapy. We evaluated the feasibility, tolerance, and impact of a pilot pharmacologic intervention with the acetylcholinesterase (AChe) inhibitor, donepezil, in pediatric brain tumor (BT) survivors at risk for neurocognitive dysfunction.. A single institution open-label pilot study was conducted in childhood BT survivors: ≥1 year from cancer treatment; and who received >23.5 Gy cranial radiation therapy (RT). Toxicity, adherence and neurocognitive outcomes were evaluated at baseline and serially during 24 weeks of donepezil, and following a 12-week washout period off drug.. From a pool of subjects, 13 were successfully contacted and screened, and 11 met all eligibility criteria to initiate donepezil at a median of 4.7 (1.9-11.9) years from RT. Seventy-two percent of patients completed the 24-week drug study visit. Despite transient gastrointestinal toxicity (vomiting and diarrhea) in 30% of patients there was no weight loss on donepezil. Significant improvement in performance was noted at 24 weeks on the Dellis-Kaplan Executive Function (D-KEF) Tower test (P < 0.001), the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML-2) Visual memory (P = 0.007), and the Number/Letter task (P = 0.018).. Donepezil was well tolerated among childhood BT survivors who had received substantial prior therapy. Based on improved executive function and memory performance in this pilot trial, a randomized placebo controlled trial of this pharmacologic agent is warranted to fully evaluate its efficacy in remediating neurocognitive dysfunction.

Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Child; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Executive Function; Female; Humans; Indans; Male; Memory; Neuropsychological Tests; Pilot Projects; Piperidines; Survivors; Treatment Outcome

Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p-CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus.

Topics: Animals; Brain Ischemia; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Death; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Donepezil; Gerbillinae; Hippocampus; Indans; Male; Maze Learning; Memory; Memory Disorders; Neurons; Neuroprotective Agents; Piperidines; Signal Transduction

Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimer's disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects.

Topics: Aged; Alzheimer Disease; Cerebrovascular Circulation; Cholinergic Fibers; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Neural Pathways; Piperidines; Regional Blood Flow; Severity of Illness Index; Time Factors

Topics: Animals; Awards and Prizes; Cognition Disorders; Cyclooxygenase Inhibitors; Diclofenac; Male; Methamphetamine; Mice; Mice, Inbred ICR; Mice, Knockout; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Substance Withdrawal Syndrome

Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)(2A)/dopamine D(2) antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT(1A) partial agonist properties, tandospirone, a selective 5-HT(1A) partial agonist, haloperidol, a D(2) antagonist, and pimavanserin, a 5-HT(2A) inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1-7), followed by a 7-day washout (day 8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT(1A) antagonists, further evidence for the importance of 5-HT(1A) receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Female; Haloperidol; Isoindoles; Lurasidone Hydrochloride; Phencyclidine; Piperazines; Piperidines; Pyridines; Pyrimidines; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Agonists; Thiazoles; Urea

The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development.

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; CHO Cells; Cognition Disorders; Cricetinae; Cricetulus; Cyclic AMP; Dogs; Drug Partial Agonism; Haplorhini; HEK293 Cells; Humans; In Vitro Techniques; Indoles; Madin Darby Canine Kidney Cells; Male; Microsomes, Liver; Permeability; Piperidines; Protein Isoforms; Pyrans; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Stereoisomerism; Structure-Activity Relationship

Life event stressors are the major vulnerability factors for the development of cognitive disorders. A vital therapeutic for stress related disorders is curcumin, derived from curry spice turmeric. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study was designed to investigate the effect of curcumin and its co-administration with piperine against chronic unpredictable stress (CUS)-induced cognitive impairment and oxidative stress in mice. Male Laca mice were subjected to undergo a battery of stressors for a period of 28 days. Vehicle/drugs were administered daily 30mins before CUS procedure. Chronic stress significantly impaired memory performance (delayed latency time to reach platform in Morris water maze as well as to reach closed arm in elevated plus maze test) and decreased locomotor activity along with sucrose consumption. Further, there was a significant impairment in oxidative parameters (elevated malondialdehyde, nitrite concentration and decreased reduced glutathione, catalase levels) and mitochondrial enzyme complex activities, along with raised acetylcholinesterase and serum corticosterone levels. Chronic treatment with curcumin (200 and 400mg/kg, p.o.) significantly improved these behavioral and biochemical alterations, restored mitochondrial enzyme complex activities and attenuated increased acetylcholinesterase and serum corticosterone levels. In addition, co-administration of piperine (20mg/kg; p.o.) with curcumin (100 and 200mg/kg, p.o.) significantly elevated the protective effect as compared to their effects alone. The results clearly suggest that piperine enhanced the bioavailability of curcumin and potentiated its protective effects against CUS induced cognitive impairment and associated oxidative damage in mice.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Chronic Disease; Cognition Disorders; Corticosterone; Curcumin; Cytochrome P-450 Enzyme Inhibitors; Dietary Sucrose; Drug Synergism; Food Preferences; Male; Maze Learning; Mice; Mice, Inbred Strains; Mitochondria; Motor Activity; Neuroprotective Agents; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Stress, Psychological; Uncertainty

Cannabinoid receptors (CBRs) play an important role in a variety of physiological functions and have been considered drug targets for obesity and psychiatric disorders. In particular, the CB1R is highly expressed in brain regions crucial to learning and memory processes, and several lines of evidence indicate that pharmacological blockade of this receptor could have therapeutic applications in the treatment of cognitive disorders. In this study, we investigated whether MK-7128 (0.1, 0.3, and 1 mg/kg, orally), a novel and selective CB1R inverse agonist, could improve learning and memory deficits induced by scopolamine (1 mg/kg, subcutaneously) in mice. The investigators also assessed CB1R occupancy in the brain to ensure target engagement of MK-7128, and showed that MK-7128 significantly improved both Y-maze spontaneous alternation and object habituation performance in scopolamine-treated mice and inhibits the binding of radioiodinated AM251 in murine cortex and hippocampus. These data indicate that MK-7128 improves cognitive performance in a model of cholinergic hypofunction and suggest that efficacy is achieved at relatively low levels of CB1R occupancy in the brain. Our results extend earlier findings suggesting a role of CB1Rs in the modulation of memory processes and a potential therapeutic application for CB1R inverse agonists in cognitive disorders.

Topics: Animals; Azetidines; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Inverse Agonism; Hippocampus; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Oxadiazoles; Piperidines; Protein Binding; Pyrazoles; Receptor, Cannabinoid, CB1; Scopolamine

There is evidence that the cholinergic system is frequently involved in the cognitive consequences of traumatic brain injury (TBI). We studied whether the brain cholinergic function is altered after TBI in vivo using PET.. Cholinergic function was assessed with [methyl-(11)C]N-methylpiperidyl-4-acetate, which reflects the acetylcholinesterase (AChE) activity, in 17 subjects more than 1 year after a TBI and in 12 healthy controls. All subjects had been without any centrally acting drugs for at least 4 weeks.. The AChE activity was significantly lower in subjects with TBI compared to controls in several areas of the neocortex (-5.9% to -10.8%, p=0.053 to 0.004).. Patients with chronic cognitive symptoms after TBI show widely lowered AChE activity across the neocortex.

Topics: Acetates; Acetylcholinesterase; Adult; Brain; Brain Injuries; Brain Mapping; Carbon Radioisotopes; Cognition Disorders; Female; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Radioligand Assay

Yokukansan (YKS) is a Japanese traditional herbal medicine and has been used for the treatment of the behavioral and psychological symptoms of dementia (BPSD). The present study aimed to clarify the effects of YKS on learning and memory impairments, and its mechanisms of action in olfactory bulbectomized (OBX) mice, one of the animal models of Alzheimer's disease (AD).. OBX or sham-operated ddY mice were treated with YKS or donepezil (DPZ), a reference drug, and their cognitive performances were tested by the modified Y-maze test, novel object recognition test, and fear conditioning test to elucidate the spatial working memory, non-spatial short-term memory, and long-term memory, respectively. After completing the behavioral experiments, the expression level of cholinergic marker proteins and the activity of acetylcholinesterase (AChE) in the brain were analyzed by western blotting and Ellman's method, respectively.. OBX caused spatial working memory and non-spatial working memory impairments that were reversed by YKS and also by DPZ; however, YKS failed to affect the long-term memory deficits. Amelioration of the spatial working memory by YKS was reversible by scopolamine, a muscarinic receptor antagonist. YKS treatment reversed OBX-induced down-regulation of choline acetyltransferase and muscarinic muscarinic M₁ receptor expression without affecting muscarinic M₃ receptor expression or AChE activity.. These results demonstrate that YKS improves short-term memory deficit caused by OBX and that the effect is at least partly mediated by muscarinic receptor stimulation and the normalization of central cholinergic systems. The present findings also suggest that YKS has a therapeutic effect not only on BPSD, but also on memory impairment of AD.

Topics: Alzheimer Disease; Animals; Choline O-Acetyltransferase; Cognition Disorders; Conditioning, Psychological; Disease Models, Animal; Donepezil; Down-Regulation; Drugs, Chinese Herbal; Fear; Indans; Learning; Male; Maze Learning; Memory; Mice; Mice, Inbred Strains; Olfactory Bulb; Phytotherapy; Piperidines; Poria; Receptors, Muscarinic; Scopolamine

To investigate how cognitive impairment is affected by the relief of bilateral carotid stenosis, chronic cerebral hypoperfusion was established through stenosis of the bilateral carotid common artery in adult Sprague-Dawley rats. Subsequently, the model rats received the intragastric placebo, donepezil (5 mg per kg), or surgery to relieve carotid stenosis after bilateral carotid common artery stenosis. After carotid stenosis was relieved, the cerebral blood flow values significantly increased, and P300 latency and escape latency in the Morris water-maze were significantly shortened. The concentrations of acetylcholine and norepinephrine in the dorsal hippocampus increased after carotid stenosis was relieved. Furthermore, P300 latency and escape latency were shortened in the relief-treated group compared to the drug-treated group, and acetylcholine levels in the relief-treated group were higher than the drug-treated group. No significant difference was found for the norepinephrine levels in the dorsal hippocampus between the relief-treated and drug-treated groups. Cognitive impairment can be significantly reduced by bilateral carotid stenosis relief, and the effect of relieving stenosis on cognitive dysfunction is superior to the effect of administering an acetylcholinesterase inhibitor.

Topics: Acetylcholine; Acoustic Stimulation; Analysis of Variance; Animals; Biogenic Monoamines; Brain Ischemia; Carotid Arteries; Carotid Stenosis; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Event-Related Potentials, P300; Hippocampus; Indans; Male; Maze Learning; Microdialysis; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

To identify the neural correlates of cognitive improvement in mild Alzheimer's disease (AD) subjects following 12 weeks of donepezil treatment.. Resting-state functional connectivity magnetic resonance imaging (R-fMRI) was used to measure the hippocampal functional connectivity (HFC) in 14 mild AD and 18 age-matched normal (CN) subjects. AD subjects were scanned at baseline and after donepezil treatment. CN subjects were scanned only at baseline as a reference to identify regions correlated or anticorrelated to the hippocampus. Before each scan, participants underwent cognitive, behavioral, and functional assessments.. After donepezil treatment, neural correlates of cognitive improvement measured by Mini-Mental State Examination scores were identified in the left parahippocampus, dorsolateral prefrontal cortex (DLPFC), and inferior frontal gyrus. Improvement in AD Assessment Scale-cognitive subscale scores correlated with the HFC changes in the left DLPFC and middle frontal gyrus. Stronger recovery in the network connectivity was associated with cognitive improvement.. R-fMRI may provide novel insights into the brain's responses to AD treatment in clinical pharmacological trials, and also may predict clinical response.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Hippocampus; Humans; Indans; Linear Models; Magnetic Resonance Imaging; Male; Nerve Net; Neuropsychological Tests; Piperidines; Recovery of Function; Reference Values; Severity of Illness Index; Treatment Outcome

Adjuvant cancer chemotherapy often causes cognitive impairment that can be long-lasting and adversely affect quality of life. The present study sought to determine if the cognitive enhancing drug, donepezil, can reduce cognitive impairment induced by a combination of methotrexate +5-fluorouracil, two drugs commonly used in cancer chemotherapy. Four groups of mice: (1) chemotherapy-only; (2) chemotherapy+donepezil; (3) saline-only; (4) saline+donepezil, were administered the following learning and memory tests: (1) standard spatial memory (SM); (2) non-spatial cued memory (CM); (3) non-matching-to-sample (NMTS) rule-learning; (4) delayed-NMTS (DNMTS). The chemotherapy-only group was impaired on the SM, NMTS, and DNMTS tasks. Chemotherapy-induced cognitive deficits were significantly reduced in the chemotherapy+donepezil group whose performance on some measures was very similar to that of the saline-only group. There was no evidence that donepezil improved the performance of saline-treated mice. The results confirm the adverse effects of chemotherapy on cognitive function and demonstrate that they can be ameliorated by donepezil, which is widely used to treat cognitive impairment in other clinical populations (e.g., Alzheimer's disease).

Topics: Analysis of Variance; Animals; Antineoplastic Combined Chemotherapy Protocols; Cognition Disorders; Cues; Disease Models, Animal; Donepezil; Female; Fluorouracil; Indans; Maze Learning; Memory; Methotrexate; Mice; Mice, Inbred BALB C; Nootropic Agents; Piperidines; Space Perception; Time Factors

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-β peptide (Aβ(1-40)) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aβ(1-40) or the control peptide Aβ(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aβ(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Aβ(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aβ(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Indans; Male; Mice; Mice, Inbred ICR; Motor Activity; Peptide Fragments; Phenylcarbamates; Piperidines; Recognition, Psychology; Rivastigmine

Topics: Adolescent; Brain Diseases; Carbon Monoxide Poisoning; Cognition Disorders; Donepezil; Humans; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Nootropic Agents; Piperidines

Topics: Aged; Cognition Disorders; Delusions; Donepezil; Dose-Response Relationship, Drug; Ectoparasitic Infestations; Humans; Indans; Male; Nootropic Agents; Piperidines

This study examined the efficacy of sertindole in comparison with a selective 5-HT(6) and a 5-HT(2A) receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats.. In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT(2A) receptor antagonist M100.907 or the selective 5-HT(6) receptor antagonist SB-742457.. The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT(6) receptor in vivo binding in striatum, although contribution from binding to 5-HT(2A) receptors in vivo in cortex may also provide an important mechanism.. The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.

Topics: Animals; Antipsychotic Agents; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluorobenzenes; Imidazoles; Indoles; Memory Disorders; Phencyclidine; Piperidines; Quinolines; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reversal Learning; Schizophrenia; Sulfones

Recently, numerous medicinal plants possessing profound central nervous system effects and antioxidant activity have received much attention as food supplement to improve cognitive function against cognitive deficit condition including in Alzheimer's disease condition. Based on this information, the effect of piperine, a main active alkaloid in fruit of Piper nigrum, on memory performance and neurodegeneration in animal model of Alzheimer's disease have been investigated. Adult male Wistar rats (180-220 g) were orally given piperine at various doses ranging from 5, 10 and 20mg/kg BW at a period of 2 weeks before and 1 week after the intracerebroventricular administration of ethylcholine aziridinium ion (AF64A) bilaterally. The results showed that piperine at all dosage range used in this study significantly improved memory impairment and neurodegeneration in hippocampus. The possible underlying mechanisms might be partly associated with the decrease lipid peroxidation and acetylcholinesterase enzyme. Moreover, piperine also demonstrated the neurotrophic effect in hippocampus. However, further researches about the precise underlying mechanism are still required.

Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Animals; Aziridines; Benzodioxoles; Choline; Cognition Disorders; Donepezil; Hippocampus; Indans; Injections, Intraventricular; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Nerve Degeneration; Neuromuscular Blocking Agents; Neuroprotective Agents; Nootropic Agents; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Space Perception; Thailand

To compare longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil hydrochloride, untreated subjects with very mild DAT, and controls without dementia.. MPRAGE sequences were collected approximately 2 years apart on two 1.5-T magnetic resonance imaging systems, yielding 2 cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields.. A dementia clinic at Washington University School of Medicine.. Subjects came from 2 sources: 18 untreated subjects with DAT and 26 controls were drawn from a previous longitudinal study; 18 treated subjects with DAT were studied prospectively, and 44 controls were drawn from a longitudinal study from the same period. Intervention Patients were prescribed donepezil by their physician.. Hippocampal volume loss and surface deformation.. There was no significant cohort effect at baseline; therefore, the 2 groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate of change of hippocampal volume or subfield deformation. Further exploration showed that compared with the untreated subjects with DAT, the treated subjects with DAT did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated subjects with DAT differed from the controls in the rates of change of hippocampal volume and CA1 and subiculum subfield deformations.. Treatment with donepezil did not alter the progression of hippocampal deformation in subjects with DAT in this study. Small sample size may have contributed to this outcome.

Topics: Aged; Alzheimer Disease; Atrophy; Brain Mapping; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Disease Progression; Donepezil; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Nerve Degeneration; Piperidines; Time Factors; Treatment Outcome

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Depressive Disorder; Disease Progression; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Topics: Adult; Alzheimer Disease; Atrophy; Cholinesterase Inhibitors; Cognition Disorders; Depressive Disorder, Major; Diagnosis, Differential; Donepezil; Drug Therapy, Combination; Female; Follow-Up Studies; Functional Laterality; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Piperidines; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome

Apolipoprotein E varepsilon4 (APOE varepsilon4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE varepsilon4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE varepsilon4 allele status on measures of cognitive and functional decline in subjects with amnestic MCI (aMCI).. A total of 516 aMCI participants aged 55-90 years who received placebo or vitamin E from the Alzheimer's Disease Cooperative Study's MCI treatment trial were evaluated. During the 36-month study period, neurocognitive and functional measures were collected. These measures were assessed over time for change and association with APOE varepsilon4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period.. APOE varepsilon4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE varepsilon4 positive had significantly more rapid decline in performance on all cognitive and functional measures except Number Cancellation and Maze tracing (P < .05). The greatest decline was seen in global measures of cognition and function including the Clinical Diagnostic Rating scale, followed by the Mini-Mental State Examination, Global Deterioration scale, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale.. These findings demonstrate that APOE varepsilon4 genotype is predictive of increased general rates of decline with global measures of cognition and function most affected. With accelerated declines in common clinical trial primary efficacy measures, APOE varepsilon4 status needs to be accounted for in treatment trials of MCI.

Topics: Aged; Aged, 80 and over; Apolipoprotein E4; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Female; Follow-Up Studies; Genotype; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Retrospective Studies; Vitamin E

Impaired antioxidant defenses are implicated in neurodegenerative disease. The plasma levels of urate, a water-soluble antioxidant, are reduced in Alzheimer's disease (AD).. We aimed to test the hypotheses that high plasma urate at baseline is associated with: (1) a reduced rate of conversion from mild cognitive impairment (MCI) to AD and (2) a lower rate of cognitive decline in MCI.. Plasma urate was obtained at baseline from 747 participants in a 3-year, randomized, double-blind, placebo-controlled study of donepezil, vitamin E or placebo for delaying the progression of MCI to AD.The association between baseline urate and conversion from MCI to AD was examined by Cox proportional hazards regression. The relationship between baseline urate and cognitive change on the cognitive subscale of the Alzheimer's Disease Assessment Scale was evaluated by longitudinal analysis.. Baseline plasma urate was not associated with the rate of conversion of MCI to AD. In the placebo arm, high plasma urate was related to a slower rate of cognitive decline over 3 years, although this was not reproduced in the other treatment arms.. While plasma urate levels did not predict the progression of MCI to AD, high urate may be associated with a reduced rate of cognitive decline in MCI patients not treated with donepezil or vitamin E. The results support the investigation of biomarkers of antioxidant status as risk factors for cognitive decline in MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Boston; Cognition Disorders; Confounding Factors, Epidemiologic; Dementia; Disease Progression; Donepezil; Female; Humans; Incidence; Indans; Male; Middle Aged; Nootropic Agents; Piperidines; Prevalence; Survival Analysis; Uric Acid; Vitamin E

Topics: Alzheimer Disease; Biomarkers; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Disease Progression; Donepezil; Humans; Indans; Neuropsychological Tests; Outcome Assessment, Health Care; Piperidines; Research Design; Treatment Failure

Cognitive deficits are commonly associated with maintenance electroconvulsive therapy (ECT). Treatment of these cognitive deficits is important but difficult. Cholinergic pathways are involved in these side effects, and donepezil, a cholinesterase inhibitor, may be useful for improvement of cognition. In this case report, we describe for the first time successful use of donepezil in treating cognitive deficits associated with maintenance ECT. The role of cholinesterase inhibitors in the treatment of cognitive deficits caused by ECT needs further studies.

Topics: Adult; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Electroconvulsive Therapy; Female; Humans; Indans; Memory Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Schizophrenia

Since acute and chronic administration of the acetylcholinesterase inhibitors, namely donepezil, improves cognitive functions in patients afflicted by mild to moderate dementia and reverses memory deficits in experimental models of learning and memory, it seemed interesting to assess the effects of chronic donepezil treatment on cognitive functions in adult rats with forebrain cholinergic depletion. Lesions were performed by means of intracerebroventricular injections of the immunotoxin 192 IgG-saporin. The cognitive functions of lesioned animals treated or not treated with donepezil were compared with those of intact animals. Cholinergic depletion affected working memory functions, weakened procedural competencies, affected the acquisition of localizing knowledge, and evoked remarkable compulsive and perseverative behaviors. In lesioned animals, chronic donepezil treatment ameliorated localizatory capabilities, performances linked to cognitive flexibility and procedural abilities. Furthermore, it attenuated compulsive deficits. The present data indicate positive effects of chronic donepezil treatment on specific cognitive performances, suggesting that an aimed use of acetylcholinesterase inhibitors, targeting some symptoms more than others, may be beneficial in the case of cholinergic hypofunction. The animal model used in the present research may provide an efficient method for analyzing cognition-enhancing drugs before clinical trials.

Topics: Acetylcholine; Analysis of Variance; Animals; Antibodies, Monoclonal; Behavior, Animal; Cholinesterase Inhibitors; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Exploratory Behavior; Indans; Male; Maze Learning; Neurologic Examination; Piperidines; Rats; Rats, Wistar; Ribosome Inactivating Proteins, Type 1; Saporins; Serial Learning

Previous studies have reported that selective sigma-1 agonists may improve cognitive abilities in experimental animals possibly via a cholinergic mechanism. However, the issue of a direct action on to sigma-1 receptors in memory-related brain areas has been much less investigated. The newly synthetised compound methyl(1R,2S/1S,2R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(+/-)-PPCC] has recently been shown to possess high affinity for the sigma-1 receptor where it specifically acts as an agonist. Here, the functional effects of (+/-)-PPCC were investigated in rat models of mild or severe cognitive dysfunction based on a sub-total (or= 90-95%) central cholinergic depletion induced by different doses of the selective immunotoxin 192 IgG-saporin injected intraventricularly. At 5-6 weeks post-surgery, the lesioned animals exhibited dose-dependent deficits in reference memory, as assessed using the Morris water maze task, whereas working memory abilities, evaluated using the radial arm water maze task, appeared equally impaired in the two dose groups. Daily treatment with (+/-)-PPCC significantly improved both reference and working memory performance in all lesioned animals but it did not affect intact or sham-lesioned subjects. In a separate test, treatment with (+/-)-PPCC reversed the learning deficits induced by the muscarinic receptor antagonist atropine sulphate in both control and mild-lesioned rats. The effect was blocked in lesioned, but not normal animals by pre-treatment with the sigma-1 antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine. The results suggest that (+/-)-PPCC may efficiently ameliorate perturbed cognitive abilities, and that these anti-amnesic effects most probably occur via a direct interaction of the compound with sigma-1 receptors.

Topics: Acetylcholine; Animals; Antibodies, Monoclonal; Atropine; Behavior, Animal; Cognition Disorders; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Ethylenediamines; Female; Maze Learning; Memory, Short-Term; Motor Activity; Muscarinic Antagonists; Nootropic Agents; Piperidines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, sigma; Ribosome Inactivating Proteins, Type 1; Saporins

This study was undertaken to examine the effects of two acetylcholinesterase inhibitors (donepezil and physostigmine) on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (14 days) administration of donepezil (1.0 mg/kg/day), but not donepezil (0.1 mg/kg/day). Furthermore, the effect of donepezil (1.0 mg/kg/day) on PCP-induced cognitive deficits was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1.0 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of donepezil. In contrast, PCP-induced cognitive deficits were not improved by subsequent subchronic (14 days) administration of physostigmine (0.25 mg/kg/day). Moreover, repeated administration of PCP significantly caused the reduction of sigma-1 receptors in the hippocampus. The present study suggests that agonistic activity of donepezil at sigma-1 receptors plays a role in the active mechanisms of donepezil on PCP-induced cognitive deficits in mice. Therefore, it is likely that donepezil would be potential therapeutic drugs for the treatment of the cognitive deficits in schizophrenia.

Topics: Analysis of Variance; Animals; Anisoles; Brain; Cell Membrane; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Hippocampus; Immunohistochemistry; Indans; Male; Mice; Mice, Inbred ICR; Phencyclidine; Physostigmine; Piperidines; Propylamines; Receptors, sigma; Recognition, Psychology; Sigma-1 Receptor; Tritium

Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer's disease (AD) and a core feature of schizophrenia. As part of our continuing efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor-one of the emerging therapeutic targets in this area. Herein, we report the identification of a novel series of 3-piperidinyl-5-sulfonylindazole derivatives as potent 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported.

Topics: Cognition Disorders; Dementia; Humans; Indazoles; Ligands; Piperidines; Receptors, Serotonin; Serotonin Antagonists; Sulfinic Acids

Topics: Aged; Aspartic Acid; Brain; Cognition Disorders; Dementia; Donepezil; Female; Humans; Indans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Phenylcarbamates; Piperidines; Psychiatric Status Rating Scales; Rivastigmine; Treatment Outcome

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Confounding Factors, Epidemiologic; Donepezil; Humans; Indans; Nootropic Agents; Observer Variation; Patient Dropouts; Piperidines; Randomized Controlled Trials as Topic

Topics: Cognition Disorders; Dementia; Depression; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

A wide range of evidences show that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship (SAR) study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Recently, acetylcholinesterase inhibitors (AChEIs) have been studied for other mechanisms of action, such as neuroprotective action and lowering of beta-amyloid (beta-amyloid). Donepezil also reduced beta-amyloid plaque in in vitro. The amyloid hypothesis is believed to be the most promising approach in the development of anti-AD drugs. We speculate the mechanism of lowering beta-amyloid by donepezil implicate alpha-secretase (alpha-secretase) enhancer.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Drug Design; Humans; Indans; Neuroprotective Agents; Piperidines; Structure-Activity Relationship

The effect of piperine, the main alkaloid from piper nigrum, on the central nervous system is not clearly known until now. In the present study, male Wistar rats were administered piperine at various doses ranging from 5, 10 and 20mg/kg BW once daily for 4 weeks and the animals were determined the neuropharmacological activity after single, 1, 2, 3 and 4 weeks of treatment. The results showed that piperine at all dosage range used in this study possessed anti-depression like activity and cognitive enhancing effect at all treatment duration. Therefore, piperine may be served as the potential functional food to improve brain function. However, further investigations about precise underlying mechanism are still required.

Topics: Alkaloids; Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Benzodioxoles; Cognition Disorders; Food Analysis; Male; Maze Learning; Mood Disorders; Motor Activity; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Swimming

Hypersexuality in Alzheimer's disease (AD) has been rarely investigated. Hypersexual behaviours should be classified as a sexual obsession and included in the "obsessive-compulsive disorder-like" spectrum. Hypersexuality has no proven treatment, although reports have described reductions of this behaviour using antiandrogen treatment, H2-receptor antagonists and antipsychotic drugs. Serotonin reuptake blockers seem to be effective in the treatment of sexual obsessions or compulsions and less on paraphilic disturbances. We present the case of a 54-year-old male patient with Alzheimer's disease with compulsive sexual behaviour as reported by his wife. A 18-FDG PET scan evidenced prevalent hypometabolism of the right hemisphere, congruent with neuropsychological evaluation. Donepezil, 10 mg per day, produced cognitive improvement but no effects on sexual behaviour. Therapy with SSRI was subsequently started (citalopram): after 60 days, the patient showed improvement in both the compulsive pursuit of sex acts and the level of frustration when refused.

Topics: Alzheimer Disease; Brain; Citalopram; Cognition Disorders; Disease Progression; Donepezil; Fluorodeoxyglucose F18; Humans; Indans; Male; Memory Disorders; Middle Aged; Mood Disorders; Nootropic Agents; Obsessive-Compulsive Disorder; Piperidines; Positron-Emission Tomography; Selective Serotonin Reuptake Inhibitors; Serotonin; Sexual Behavior; Sexual Dysfunctions, Psychological; Treatment Outcome

Cognitive dysfunctions are being recognized as a major roadblock to functional recovery in patients with bipolar disorders. Little is known about the treatment of these cognitive dysfunctions. Donepezil, approved to treat memory dysfunction in Alzheimer's disease, is evaluated for cognitive dysfunctions common in bipolar disorder. Of concern is some evidence that donepezil may trigger affective instability.. All bipolar disordered patients in a private practice setting treated with donepezil for memory problems were analyzed. Patients were assessed for memory improvement and change in psychiatric status with the Clinical Global Impression of Improvement Scale.. Thirty-nine of 58 patients (67%) reported improvement with a mean score of 1.82 (standard deviation+/-0.82). Nine treatments were stopped because of side effects and 4 showed no response. No bipolar I patient received benefits. Thirty-six of 43 (84%) of bipolar II patients showed improvement. Fifty percent of bipolar NOS showed improvement. Four bipolar I patients (57%), 1 bipolar II patient (2%) and 2 bipolar NOS patients (25%) stopped donepezil due to worsening affective symptoms.. This is a naturalistic case series with a single evaluator. Other medications used in treatment were changed as clinically indicated.. This case series suggests utility for donepezil in the treatment of cognitive problems associated with bipolar II disorder and bipolar disorder NOS. Bipolar I patients showed no improvement and a concerning trend to destabilize with donepezil treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bipolar Disorder; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Patient Dropouts; Piperidines; Private Practice; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome

We have previously reported that an injection of a single, extremely low dose (0.001 mg/kg) of delta 9-tetrahydrocannabinal (THC, the major psychoactive ingredient of marijuana) to mice deteriorated their performance in the Morris water maze test 3 weeks later. In the present study we verify our original findings and show that the long-term cognitive deficits that are induced in mice by a low dose of THC are even more pronounced in another behavioral test-the water T-maze. This effect was abolished by the CB1 receptor antagonist SR141716A, indicating the involvement of CB1 receptors. In an attempt to find a biochemical correlate to these deleterious consequences of such a low dose of THC, we investigated its effect on the activation of extracellular signal-regulated kinase (ERK1/2) in the cerebellum and hippocampus of the mice, two brain regions that were shown to participate in spatial learning. A significant increase in ERK1/2 phosphorylation was found in the cerebellum of mice 24 h following the injection of 0.001 mg/kg THC. These findings lead to further studies into the neuronal mechanisms underlying the long-term deleterious effects of THC and should be taken into consideration when evaluating the therapeutic benefits of cannabinoid drugs.

Topics: Animals; Behavior, Animal; Blotting, Western; Brain Chemistry; Cognition Disorders; Dronabinol; Enzyme Induction; Extracellular Signal-Regulated MAP Kinases; Hallucinogens; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Piperidines; Psychomotor Performance; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The most commonly used model of Down syndrome, the Ts65Dn (TS) mouse, is trisomic for most of the region of MMU16 that is homologous to HSA21. This mouse shares many phenotypic characteristics with people with Down syndrome including behavioral and cognitive alterations. The objective of this study was to analyze the ability of two drugs that improve cognition in different experimental models, the acetylcholinesterase inhibitor donepezil and the non-competitive GABA(A) antagonist pentylenetetrazole (PTZ), to improve the cognitive deficits found in TS mice. The drugs were administered p.o. to TS and CO mice for 8 weeks and a behavioral characterization was performed. Sensorimotor abilities, including vision, hearing, strength and motor coordination, as well as locomotor activity in the home cage, were not modified by any chronic treatment in TS and CO mice. TS mice showed altered equilibrium in the aluminium rod, and this effect was larger under PTZ treatment. This result may indicate a potential adverse effect of PTZ in Ts65Dn mice. Learning and memory were evaluated in TS and CO mice after both treatments in the Morris water maze. Donepezil administration did not modify learning and memory in animals of any genotype. On the other hand, PTZ administration rescued TS performance in the Morris water maze.

Topics: Acetylcholine; Animals; Brain; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Disease Models, Animal; Donepezil; Down Syndrome; Drug Administration Schedule; GABA Antagonists; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Indans; Male; Maze Learning; Memory Disorders; Mice; Mice, Neurologic Mutants; Neural Inhibition; Pentylenetetrazole; Piperidines; Receptors, GABA-A; Treatment Outcome; Trisomy

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Neuropsychological Tests; Piperidines; Severity of Illness Index; Treatment Outcome

Topics: Brain Injuries; Cognition Disorders; Donepezil; Humans; Indans; Male; Middle Aged; Nootropic Agents; Piperidines

Topics: Aged; Anti-Anxiety Agents; Antipsychotic Agents; Benzodiazepines; Catatonia; Chlorpromazine; Cholinesterase Inhibitors; Cognition Disorders; Creatine Kinase; Dementia; Disease Progression; Donepezil; Female; Humans; Indans; Lorazepam; Muscle Rigidity; Neuroleptic Malignant Syndrome; Olanzapine; Piperidines; Recurrence; Risperidone

Many conditions adversely affecting learning, memory, and cognition are associated with reductions in forebrain acetylcholine (ACh), most notably aging and Alzheimer's disease. In the current study, we demonstrate that bilateral depletion of neocortical and hippocampal ACh in rats produces deficits in a spatial learning task and in a recently described, delayed visual matching-to-sample task. Oral administration of the novel nitrate, GT1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), and the acetylcholinesterase inhibitor, donepezil, reversed the cognitive deficits in both memory tasks in a dose-dependent manner. GT1061 was superior in the delayed matching-to-sample task. GT1061 was absorbed rapidly after oral administration, crossed the blood brain barrier, and achieved brain concentrations that were slightly higher than those found in plasma. The activity of GT1061 was NO mimetic: soluble guanylyl cyclase (sGC) was activated, but selectivity was observed for sGC in the hippocampus relative to the vasculature; and hippocampal levels of phosphorylated ERK1/2, which is a postulated intermediary in the formation of long-term memory, were increased. The beneficial effect on visual and spatial memory task performance supports the concept that stimulating the NO/sGC/cGMP signal transduction system can provide new, effective treatments for cognitive disorders. This approach may be superior to that of current drugs that attempt only to salvage the residual function of damaged cholinergic neurons.

Topics: Acetylcholine; Analysis of Variance; Animals; Behavior, Animal; Choice Behavior; Cognition Disorders; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Female; Indans; Male; Maze Learning; Mitogen-Activated Protein Kinase 3; Nitrates; Nootropic Agents; Phosphorylation; Piperidines; Prosencephalon; Protein Binding; Psychological Tests; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Reaction Time

The successful cloning and functional expression of the histamine H(3) receptor in the late 1990 s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H(3) antagonists in models of CNS disorders. High-throughput screening identified several series of lead compounds, including a series of imidazopyridines, which led to JNJ-6379490, a compound with high affinity for the human H(3) receptor. Analysis of structural features common to several series of non-imidazole H(3) receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H(3) antagonist with good in vitro and in vivo efficacy but with an undesirable long half-life. However, further modifications of the template provided an understanding of the effect of structural modifications on pharmacokinetic properties, ultimately affording several additional series of compounds including JNJ-10181457, a compound with an improved pharmacokinetic profile. These compounds allowed in vivo pharmacological evaluation to show that H(3) antagonists promote wakefulness, but unlike modafinil and classical psychostimultants, they do not increase locomotor activity or produce any alteration of the EEG power spectral activity in rats. H(3) antagonists also increase extracellular acetylcholine and norepinephrine but not dopamine in rat frontal cortex and show efficacy in various models of learning-memory deficit. In addition, cFos immunoreactivity studies show H(3) antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H(3) antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders.

Topics: Animals; Cloning, Molecular; Cognition Disorders; Diamines; DNA, Complementary; Histamine Antagonists; Humans; Male; Morpholines; Narcolepsy; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3

The purpose of this work is to prepare donepezil microparticles (DM) and evaluate its advantage as a sustained release delivery system with subcutaneous injection once a month. DM was prepared using poly (d,l-lactide-co-glycolide) (PLGA) by an oil-water emulsion solvent evaporation technique. DM showed the loading ratio 13.2+/-2.1% (w/w) and yield 54.8+/-0.8% with mean particle size about 75mum. In vitro release of DM showed that donepezil completely released within 28 days in water, but the cumulative release percentages up to day 30 were 98.4% and 49.1% for phosphate buffer saline (PBS, pH 5.8) and PBS (pH 7.4), respectively. The in vivo experiment demonstrated that DM (90mg/kg) produced a sustained release process in rats, and reached steady-state concentration at day 8 and maintained until day 27 with steady-state levels of donepezil between 130.3+/-7.8 and 121+/-9.8ng/ml, which was accordance with that of free donepezil by oral application route (3mg/kgday). DM (90mg/kg) by subcutaneous infusion in rats produced the same pharmacological role as free donepezil (3mg/kgday) by oral application route. These results implicated that DM as a sustained release delivery strategy could substitute for its oral formulation for therapy of AD and come true its administration once a month.

Topics: Alzheimer Disease; Animals; Capsules; Cholinesterase Inhibitors; Cognition Disorders; Delayed-Action Preparations; Diffusion; Donepezil; Drug Evaluation, Preclinical; Indans; Particle Size; Piperidines; Rats; Treatment Outcome

Topics: Alzheimer Disease; British Columbia; Clinical Pharmacy Information Systems; Cognition Disorders; Donepezil; Drug Utilization; Health Services Needs and Demand; Humans; Indans; Pharmacology, Clinical; Piperidines; Practice Patterns, Physicians'

Topics: Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Galantamine; Humans; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Stress Disorders, Post-Traumatic; Stroke; Veterans

AD is characterized by a widespread cognitive impairment and deficit in functional competency to perform activities of daily living (ADL). The longitudinal reliability of cognitive and functional performance indices and the strength of relationship between patients cognitive impairment and their functional competence are still open issues. The aim of this study has been to evaluate, in a selected sample of patients with AD treated with AChEl, the slopes of cognitive impairment and disability. Among 249 AD patients, according to DSM-IV criteria, with presence/absence of associated vascular lesions (AD+VD), eligible for AChEl treatment, we selected subjects with mild to moderate cognitive impairment, without high comorbidity and severe psychiatric disease, with caregiver who resided with, or had frequent contact with the patient. Patients that changed treatment shifting from one AChEl to another, that didn't tolerate inhibitors (drop-out), and that presented behavioral and psychological symptoms of dementia (BPSD) requiring neuroleptic treatment during the study period were excluded from the final analysis. A sample of 99 subjects (30 males, 69 females; mean age of 79.4+/-5.0 years), completing a 15 months follow-up was considered. Cognitive performance remained stable after 15 months of treatment, but disability increased. No difference was found due to the AChEl compound used. The same hold true for the subgroups with presence/absence of a vascular components, whereas subgroup with mild cognitive performance showed a cognitive decline, parallel to the functional one. Our data underline the efficacy of AChEl in the treatment of AD with presence/absence of vascular component. Nevertheless, the judgement on the level of efficacy of AChEl could be biased by the level of reliability of the indices considered.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Disability Evaluation; Donepezil; Female; Follow-Up Studies; Galantamine; Humans; Indans; Male; Mental Disorders; Neuropsychological Tests; Phenylcarbamates; Piperidines; Rivastigmine; Severity of Illness Index

In the present study, we assessed whether concurrent treatment with low doses of cilostazol and donepezil effectively improve memory deficits in association with amelioration of the pathological changes in the white matter of rats subjected to permanent ligation of bilateral common carotid arteries (BCCAL). The escape latency in Morris water maze test was significantly increased at 7, 14 and 21 days in rats subjected to BCCAL. At 21 days after ligation, the white matter lesions including vacuole formation with rarefaction were increased in the optic tract and corpus callosum accompanied by a large increase in glial fibrillary acidic protein (GFAP) immunoreactivity with significantly decreased CNPase-positive oligodendrocytes, all of which were significantly alleviated by the combination therapy with suboptimal doses of cilostazol (30 mg/kg orally) and donepezil (0.3 mg/kg intraperitoneally). The phosphorylated cyclic AMP response element-binding protein (p-CREB)- and Bcl-2-positive cells were significantly decreased following BCCAL, which were completely restored by the combination therapy, whereas the monotherapy with cilostazol or donepezil showed marginal effect. In conclusion, concurrent treatment with cilostazol and donepezil effectively prevented the occurrence of neuropathological alterations in the white matter by activation of p-CREB and Bcl-2, thereby resulting in improvement of spatial learning memory in rats subjected to chronic cerebral hypoperfusion.

Topics: Animals; Behavior, Animal; Brain; Brain Ischemia; Choline O-Acetyltransferase; Cilostazol; Cognition Disorders; CREB-Binding Protein; Donepezil; Drug Combinations; Indans; Male; Maze Learning; Neuroprotective Agents; Piperidines; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Sprague-Dawley; Tetrazoles; Vesicular Acetylcholine Transport Proteins

We examined the frequency of cognitive impairment using the mini-mental-status examination (MMSE), as well as cerebral perfusion using single photon emission computed tomography (SPECT) in elderly diabetic patients. Written consent was obtained from all patients prior to their inclusion in this study. An MMSE score of 26 or less was adopted as an indication of cognitive impairment. Following an initial study, a 3-month study incorporating the use of MMSE and SPECT was performed in subjects, some of whom were taking donepezil hydrochloride. Of the 92 subjects enrolled in this study, 38% exhibited cognitive functional impairment and 18% earned MMSE scores of 23 or lower that were indicative of dementia. With regard to their cerebral blood flow pattern as determined by SPECT 217, 31.4 and 34.2% of subjects showed parieto-temporal hypoperfusion, asymmetrical hypoperfusion and fronto-temporal hypoperfusion patterns of abnormalities, respectively; 11.4% displayed unclassifiable findings and 8.5% showed no detectable abnormalities. No significant differences were seen in patients that were taking donepezil hydrochloride compared to those who were not. The incidence of cognitive functional impairment in elderly, diabetic patients was significantly elevated and was accompanied by a reduction in cerebral blood flow in the fronto-temporal region, as determined by SPECT.

Topics: Aged; Brain; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition Disorders; Diabetes Mellitus, Type 2; Donepezil; Female; Humans; Incidence; Indans; Male; Mental Status Schedule; Piperidines; Tomography, Emission-Computed, Single-Photon

Topics: Aged; Alzheimer Disease; Cognition Disorders; Donepezil; Dreams; Female; Follow-Up Studies; Humans; Indans; Mental Status Schedule; Nootropic Agents; Piperidines

Six migraine patients experienced significant topiramate-related cognitive and language dysfunction that improved with donepezil treatment and allowed uninterrupted topiramate use. These patients represent the first report of topiramate-related cognitive and language dysfunction that improved with a cholinesterase inhibitor. Although, the mechanism responsible for this effect is uncertain, cholinesterase inhibition resulting in cholinergic augmentation and enhanced cognition probably account for some if not most of the improvement.

Topics: Adult; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Fructose; Humans; Indans; Language Disorders; Male; Middle Aged; Migraine Disorders; Piperidines; Topiramate; Treatment Outcome

Topics: Alzheimer Disease; Brain Neoplasms; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Radiation Injuries; Radiotherapy

We present a case that promotes early intervention and pharmacological treatment for the neuropsychiatric sequelae (frontal lobe syndrome, including cognitive impairment and aggressive behavior) associated with traumatic brain injury (TBI) and delirium. The patient, who sustained significant systemic complications related to his trauma, was previously diagnosed with alcohol and drug dependence and antisocial personality disorder. These antecedent conditions and prolonged systemic complications likely played a complicating role in his course of recovery.

Topics: Adult; Aggression; Amantadine; Cognition Disorders; Conduct Disorder; Donepezil; Frontal Lobe; Humans; Indans; Male; Neurotransmitter Agents; Nootropic Agents; Piperidines; Valproic Acid

Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions.. The objective of the present experiments was to explore the effects of donepezil (Aricepttrade mark), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction.. The effects of donepezil were assessed in Sprague-Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests.. Scopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (approximately 20-50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (approximately 3-10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (approximately 1% of the variance).. These results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.

Topics: Animals; Attention; Cholinesterase Inhibitors; Cognition Disorders; Conditioning, Psychological; Donepezil; Indans; Male; Maze Learning; Memory; Muscarinic Antagonists; Piperidines; Psychomotor Disorders; Rats; Rats, Sprague-Dawley; Scopolamine

Topics: Aged; Alzheimer Disease; Atrophy; Brain; Cognition Disorders; Disease Progression; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Tardive dyskinesia and other delayed-onset abnormal involuntary movement disorders may occur as a result of the use of psychotropic drugs. A distinction is usually made between classic tardive dyskinesia (TD) (orobuccal-lingual-facial) and tardive dystonia, tardive tremor (TT), tardive akathisia, and other related syndromes. In spite of the development of atypical antipsychotics with fewer side effects, tardive movement disorders nevertheless continue to present a significant clinical and therapeutic challenge. Several reports have suggested that donepezil may be helpful in the treatment of TD.. A preliminary study was conducted of 7 patients (5 women and 2 men) enrolled over a period of 6 months who had been experiencing TT for a period of at least 1 year. The ages of the patients ranged from 64 to 79 years, and all patients were on stable antipsychotic therapy. Donepezil was added to their usual treatment for 8 weeks. The severity of patients' extrapyramidal symptoms was assessed using the tremor subscale of the Simpson-Angus Scale (SAS) and self-rated with a modification of the Clinical Global Impressions scale, the Subjective Clinical Improvement Impression scale. The clinical response was evaluated by comparing the rating scores at baseline prior to donepezil treatment and every 2 weeks thereafter.. The addition of donepezil (up to 10 mg/day) was associated with a clinically significant improvement (from 37.5% to 63.6%) on the SAS tremor subscale following 4 weeks of therapy. Only 1 patient discontinued follow-up due to side effects.. The results suggest that donepezil may be effective in the treatment of TT, and this finding should be evaluated further by a randomized controlled study.

Topics: Aged; Antipsychotic Agents; Basal Ganglia Diseases; Bipolar Disorder; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Dyskinesia, Drug-Induced; Female; Geriatric Assessment; Hospitalization; Humans; Indans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome

To report 2 cases of patients with Down syndrome and severe cognitive impairment who gained dramatic improvements in quality of life (QOL) upon donepezil treatment.. Case 1. A 38-year-old woman with Down syndrome, diagnosed with secondary progressive dementia when her mental state had deteriorated rapidly after graduation from junior high school, started donepezil treatment. The loading dose was 3 mg/day and was increased to 5 mg/day for maintenance. One month after the dose was increased, adverse effects such as soft stool and urinary incontinence appeared. These adverse effects disappeared when the dose was decreased again to 3 mg/day. Her QOL improved dramatically with this minimal dose. She recovered verbal and written communication skills that she had lost for the past 21 years. Case 2. A 22-year-old man with Down syndrome, who had been diagnosed as having severe mental retardation, was put on donepezil therapy. Both loading and maintenance doses were 3 mg/day. His QOL had also dramatically improved, with some recovery in verbal communication. Transient agitation/violence and transient muscle weakness appeared during the first few months of treatment.. Patients with Down syndrome may be more sensitive to donepezil therapy than others and may benefit from this medicine, although they may also have adverse effects more frequently.. Donepezil may be a useful medicine for some patients with Down syndrome with severe cognitive impairment or mental retardation if the adverse effects are manageable.

Topics: Adult; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Down Syndrome; Female; Humans; Indans; Intellectual Disability; Male; Piperidines; Quality of Life

We have investigated the effect of 2-arachidonylglyceryl-ether (Noladin) on food consumption, weight, activity, and cognitive function in mice during diet restriction for 17 days and subsequent ad libitum feeding for 32 days. Female Sabra mice were given food for 2.5 h/day (equal to 60% diet restriction), received Noladin (0.001, 0.01, 0.1 mg/(kg day) intraperitonially (i.p.)) with or without the CB1 antagonist SR141716A (1 mg/kg i.p.) during days 3-17. Noladin (0.001 mg/kg) significantly increased food consumption without a change in body weight, probably due to increased activity and there was no change in cognitive function. A higher dose (0.1 mg/kg) did not affect food consumption, but increased activity and slightly decreased weight 32 days after termination of Noladin administration; however, cognitive deterioration was observed. At all doses tested, Noladin did not affect weight during the diet-restriction period, whereas the CB1 antagonist (with or without Noladin) caused a very significant decline in weight in this phase. Weight catch-up was observed 1 month after administration of Noladin was discontinued. Weight at day 32 after the termination of Noladin (0.1 mg/(kg day)) treatment was 5% less than control. Female C57BL/6 mice (same protocol, with 0.001 mg/(kg day) Noladin) gave similar results to 0.1 mg/kg in Sabra mice as regards weight. CB1 antagonist treatment caused very significant decline in both weight and food consumption; cognition and activity were unchanged. These results indicate that Noladin has a significant dose-dependent effect on food consumption, cognition and weight maintenance after weight loss. Low doses of Noladin may possibly allow an increase in food intake without a gain in weight after dieting. Thus, Noladin could be of potential clinical benefit in treating disorders of body weight. Noladin seems to signal food consumption and weight through CB1 receptors based on effects observed with the CB1 antagonist, while the cognition and activity are probably mediated by non-cannabinoid receptors.

Topics: Animals; Body Weight; Cannabinoid Receptor Modulators; Cognition; Cognition Disorders; Dose-Response Relationship, Drug; Eating; Endocannabinoids; Feeding and Eating Disorders; Female; Food Deprivation; Glycerides; Mice; Mice, Inbred C57BL; Motor Activity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Species Specificity; Weight Gain

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Female; Humans; Indans; Magnetic Resonance Spectroscopy; Occipital Lobe; Piperidines; Predictive Value of Tests; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Treatment Outcome

Despite the well-described attention and short-term memory enhancing effects of H3 receptor antagonists, and evidence to suggest a close relationship between central histaminergic and cholinergic systems, there is a paucity of evidence for a role for H3 receptor blockade in spatial learning. To address this, we investigated two H3 receptor antagonists in a visual discrimination water maze in rats, and in a Barnes circular maze in mice. Thioperamide and ciproxifan significantly attenuated a scopolamine-induced deficit in the water maze task, while only ciproxifan showed a modest attenuation in the Barnes maze. Taken together, these data suggest a role for H3 receptors in spatial learning that appears to be task-dependent.

Topics: Animals; Cognition Disorders; Discrimination Learning; Escape Reaction; Histamine Antagonists; Imidazoles; Male; Maze Learning; Mice; Mice, Inbred C57BL; Models, Animal; Muscarinic Antagonists; Piperidines; Rats; Rats, Long-Evans; Receptors, Histamine H3; Scopolamine; Spatial Behavior

Topics: Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Cholinesterase Inhibitors; Cognition Disorders; Disease Progression; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Treatment Failure; Vitamin E

Topics: Alzheimer Disease; Cognition Disorders; Donepezil; Female; Humans; Indans; Nootropic Agents; Piperidines; Vitamin E

Topics: Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Humans; Indans; Piperidines; Treatment Failure; United Kingdom

The purpose of this study was to investigate the effects of donepezil, a cholinergic agent, on chronic cognitive impairment due to traumatic brain injury (TBI). Chronic patients underwent two standardized neuropsychological evaluations--one before and the other 3 months following treatment with donepezil. Together with global inventories that appraised behaviour, fatigue, anxiety and depression, these evaluations also assessed executive functioning, memory and attention. Of the 10 patients who followed the therapy, 8 reported subjective improvement in at least one cognitive domain following therapy and most of them reported better functioning in everyday activities. This effect was supported by a slight global improvement when considering the global score of the different affectivo-behavioural scales. At the neuropsychological level, although we could observe a slight improvement in the majority of the considered tests, significant positive changes were mainly found in tests assessing speed of processing, learning and divided attention. These findings suggest that donepezil may lead to better general functioning and improve attentional skills in patients with chronic TBI.

Topics: Adult; Brain Injuries; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Treatment Outcome

Mild cognitive impairment (MCI) refers to memory deficits in excess of normal aging, but not sufficient for the diagnosis of Alzheimer's disease (AD). In general, patients with MCI are not disabled and have no other obvious cognitive deficits other than memory. Many studies have shown that patients with MCI are more likely to progress to AD than age-matched controls. Drug therapy to prevent or delay deterioration in patients with MCI has been tested only very recently. The results of three clinical trials are discussed. One of two trials with donepizil suggests that donepizil may delay onset of AD, but the effect is modest and the side effects are problematic. Galantamine appeared to be associated with excess deaths, and vitamin E was not effective. No medications are currently indicated for the prevention of dementia in patients with MCI.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Disease Progression; Donepezil; Humans; Indans; Piperidines

Cholinesterase inhibitors improve cognitive functioning in Alzheimer disease (AD). The authors studied, with functional magnetic resonance imaging (fMRI), the neural mechanism by which this cholinergic enhancement improves memory encoding in AD over longer time periods.. Brain activation was measured in 10 patients with AD and 10 healthy elderly comparison subjects with fMRI while they were encoding novel faces. Patients were scanned again after a 10-week open treatment with the cholinesterase-inhibitor donepezil.. Neuropsychologically-tested memory performance improved during the treatment phase in the patients. During the encoding of novel faces, elderly comparison subjects showed more activation in the right fusiform gyrus than the group of AD patients. After a 10-week treatment with donepezil, the fusiform gyrus was also activated in patients, similar to the comparison group.. The right fusiform gyrus is associated with the processing of faces. Cholinergic enhancement augments selective attention by increased selectivity of perceptual responses in patients with AD. This mechanism may contribute to a more efficient processing of the attended stimulus and thus be a mechanism underlying clinical improvement of cognitive functioning. These promising preliminary findings need to be confirmed in a larger, controlled trial in which both fMRI and attention measures serve as outcomes.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Mapping; Cerebral Cortex; Cholinesterase Inhibitors; Cognition Disorders; Dominance, Cerebral; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Face; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Memory, Short-Term; Middle Aged; Pattern Recognition, Visual; Piperidines; Prosopagnosia; Psychomotor Performance

Despite available pharmacotherapeutics, a number of youths with attentiondeficit/ hyperactivity disorder (ADHD) continue to experience residual symptoms and prominent executive function (EF) deficits resulting in impairment in multiple domains. We sought to determine if donepezil, used adjunctively to stimulant medication, would improve residual symptoms of ADHD and EF deficits.. In a 12-week open trial, we treated 7 children and 6 adults who had ADHD and evidence of further EF deficits with adjunctive donepezil. All subjects were stabilized on stimulants, at which time donepezil was initiated at 2.5 mg daily and increased to a maximum of 10 mg over the 12-week trial.. Of 13 subjects receiving medication, 7 completed the trial. There was no clinically or statistically significant improvement in the ADHD Rating Scale and the Executive Function Checklist, our primary outcome measures. A majority of individuals experienced nonserious adverse events.. Results of this small open study suggest that donepezil augmentation of stimulants is not well tolerated and does not appear useful for the treatment of residual ADHD and/or EF deficits.

Topics: Adolescent; Adult; Amphetamines; Antimanic Agents; Attention Deficit Disorder with Hyperactivity; Child; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Female; Humans; Indans; Male; Methylphenidate; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychometrics; Treatment Outcome

Cerebrovascular disease (CVD) and ischemic brain injury secondary to cardiovascular disease are common causes of dementia and cognitive decline in the elderly. CVD also contributes to cognitive loss in Alzheimer disease (AD).. Progress in understanding vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising symptomatic and preventive treatments. Cholinergic deficits in VaD due to ischemia of basal forebrain nuclei and cholinergic pathways can be treated with cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil and galantamine in patients with VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior, and activities of daily living. The N-methyl-D-aspartate receptor antagonist memantine stabilized progression of VaD compared with placebo. Primary and secondary stroke prevention, in particular with control of hypertension and hyperlipidemia, can decrease VaD incidence.. From a public health viewpoint, recognition of VCI before the development of dementia and correction of vascular burden on the brain may lead to a global decrease of incident dementia.

Topics: Carbamates; Cardiovascular Diseases; Cerebrovascular Disorders; Cholinesterase Inhibitors; Cognition Disorders; Controlled Clinical Trials as Topic; Dementia, Vascular; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Risk Factors; Rivastigmine; Stroke; Terminology as Topic

The present study aimed to assess the initial effects of donepezil hydrochloride (DPZ) on various aspects of cognitive function in patients with dementia of Alzheimer's type (DAT) using the Japanese version of the Wechsler Adult Intelligence Scale-Revised (WAIS-R). DPZ was administered to 47 patients with mild-to-moderate DAT (D group). The control group comprised 61 patients who had been followed up before DPZ was released for use (C group). Both groups underwent WAIS-R testing, before and after 10 months of treatment with DPZ for group D, and at time of diagnosis of DAT and 10 months later for group C. D and C groups did not differ significantly in terms of gender ratio, years of education, age at onset of DAT, age at administration of DPZ or at diagnosis of DAT, severity of dementia, MMSE score, presence of behavioral and psychological symptoms of dementia, concomitant use of psychotropic medication, or initiation of rehabilitation. No significant differences were found between D and C groups in verbal (V), performance (P) or full-scale (F) intelligence quotient (IQ), or in six verbal subtest scores of VIQ and five performance subtest scores of PIQ on WAIS-R, before administration of DPZ or at diagnosis of DAT. For differences between each score on WAIS-R at diagnosis of DAT or before administration of DPZ and 10 months later, DPZ inhibited decreases in FIQ and in VIQ, PIQ, vocabulary, similarities, picture arrangement and object assembly subtest scores on WAIS-R. These indices are related to concept formation and abstract thinking, which form part of executive function. DPZ effectively prevented decline of cognitive function, particularly executive function, in patients with DAT.

Topics: Aged; Alzheimer Disease; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Nootropic Agents; Piperidines; Wechsler Scales

A 75-year old man with a 40-year history of alcoholism was admitted to the hospital for intoxication and inability to care for himself. He had been admitted frequently in the past for detoxification and rehabilitation. The patient had no family history of Alzheimer's disease, no history of head injury, and single-photon emission computed tomography showed no typical findings of Alzheimer's disease. His cognitive function was impaired. He was treated with donepezil for alcohol-related dementia, and 3 months later, his cognitive function had improved. More research is needed to confirm donepezil's role in treating alcohol-related dementia.

Topics: Aged; Alcohol-Related Disorders; Cognition Disorders; Donepezil; Drug Administration Schedule; Humans; Indans; Injections; Male; Piperidines; Time Factors; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency

Cholinesterase inhibitors positively affect cognition in Alzheimer's disease (AD) and other conditions, but no controlled functional MRI studies have examined where their effects occur in the brain. We examined the effects of donepezil hydrochloride (Aricept) on cognition and brain activity in patients with amnestic mild cognitive impairment (MCI), a diagnosis associated with a high risk of developing AD. Nine older adults with MCI were compared with nine healthy, demographically matched controls. At baseline, patients showed reduced activation of frontoparietal regions relative to controls during a working memory task. After stabilization on donepezil (5.7 +/- 1.7 weeks at 10 mg) patients showed increased frontal activity relative to unmedicated controls, which was positively correlated with improvement in task performance (r = 0.49, P = 0.05) as well as baseline hippocampal volume (r = 0.62, P < 0.05). The patients' overall cognitive function was stable or improved throughout the study. Short-term treatment with a cholinesterase inhibitor appears to enhance the activity of frontal circuitry in patients with MCI, and this increase appears to be related to improved cognition and to baseline integrity of the hippocampus. These relationships have implications for understanding the mechanisms by which cognition-enhancing medications exert their effects on brain function and for the use of functional MRI in early detection and treatment monitoring of AD and MCI.

Topics: Aged; Alzheimer Disease; Case-Control Studies; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Piperidines

To describe the assessment and treatment of an elderly woman with parkinsonism, progressive memory and cognitive deficits, and visual hallucinations.. The patient presented with a 10-year history of hand tremors, an 8-year history of short-term memory problems, and a 3-4-year history of visual hallucinations. Treatment with donepezil and rivastigmine (successively) did not produce the desired benefits. Then she was started on galantamine 4 mg b.i.d. (escalated to 8 mg b.i.d.).. The patient's social interaction improved and cognitive decline appeared to be stabilized; hallucinations and agitation were also better controlled.. By current criteria, this subject would be labeled as having Parkinson's disease with dementia, although she exhibited the core features of dementia with Lewy body disease. As suggested in previous studies, cholinesterase inhibitors may be effective in treating psychotic symptoms; however, all currently available agents may not be equally effective.

Topics: Aged; Aged, 80 and over; Carbamates; Cognition Disorders; Donepezil; Drug Resistance; Female; Galantamine; Hallucinations; Humans; Indans; Lewy Body Disease; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Psychomotor Agitation; Rivastigmine; Social Behavior

To evaluate the effects of administering Donepezil during inpatient rehabilitation for individuals with TBI.. Retrospective, age and injury severity matched, mixed between-within subjects analysis.. Thirty-six patients with moderate-to-severe TBI admitted to acute rehabilitation within 90 days of injury. Main outcome measures included FIM cognitive total scores and rehabilitation lengths of stay.. Initiation of Donepezil administration beginning at 5 mg daily. Dose titration and continuation based on perceived clinical response.. No differences in cognitive improvement were observed between the Donepezil treatment group and the matched control group. Sub-set analyses suggested that administration of Donepezil early in the rehabilitation stay was significantly related to higher rates of cognitive improvement.. Preliminary evidence suggests that Donepezil administration early in the rehabilitation stay may have advantageous treatment effects. A prospective, randomized, placebo-controlled clinical trial with standard timing, dosage and treatment duration is recommended to further evaluate treatment efficacy.

Topics: Adult; Analysis of Variance; Brain Injuries; Cognition Disorders; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Length of Stay; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Rehabilitation Centers; Retrospective Studies; Treatment Outcome

Donepezil (Aricept), a long-acting cholinesterase inhibitor, is widely used in the treatment of Alzheimer's disease to improve cognition and memory. Many drugs within the class of cognition-enhancing agents, both currently approved medications and those under development, have clinical indications narrowly relegated to Alzheimer's disease. The purpose of this study was to determine whether the efficacy attributed to donepezil in its ability to improve delayed matching accuracy by monkeys was independent of age. Male and female rhesus monkeys (n = 17) ranging from 9to 29 yr of age were administered donepezil (10, 25, 50, and 100 microg/kg, im) during 4 discrete test days. Donepezil treatment improved average task accuracy, but intersubject variability prohibited statistical significance. When animals were considered individually, the most effective dose of donepezil was associated with a highly significant increase in group task performance that was consistent with enhanced recall during testing. The variability associated with the dose-response analysis was attributable primarily to subject age, such that older monkeys required higher doses of donepezil. Yet at doses that were effective in all subjects, there was no relationship between age and the improvement in task accuracy. Likewise, there was no association between baseline task proficiency and improvement in task accuracy.

Topics: Age Factors; Aging; Animals; Cognition; Cognition Disorders; Donepezil; Dose-Response Relationship, Drug; Female; Indans; Macaca mulatta; Male; Memory Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Recovery of Function; Sex Factors; Treatment Outcome

Topics: Alzheimer Disease; Cognition Disorders; Humans; Indans; Insurance Coverage; Medicare; Piperidines; Tomography, Emission-Computed

Topics: Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Memory; Multiple Sclerosis; Nootropic Agents; Piperidines

To observe the effect of small dose donepezil (Aricept) on the cognition status and the changes of metabolites in brain tissue in patients with amnestic mild cognitive impairment (aMCI) in order to find out the effective way to prevent and cure dementia.. 33 patients with aMCI were selected. There were 21 cases in a treatment group taking 2.5 mg of Aricept daily for 3 months and 12 cases in a control group taking basic internal medicines. Before and after taking the medicine, cognition tests such as clinical memory test, basic IQ test, language fluency test and drawing-clock test were carried out. Before and after treatment, magnetic resonance spectroscopy (MRS) in hippocampus region was carried out in 5 patients of the treatment group.. Compared with the results before treatment, the memory IQ test, mini-mental state examination (MMSE) total scores as well as delayed memory scores in the treatment group were improved significantly after treatment. The difference was statistically significant. MRS results indicated that after treatment NAA/Cr and Cho/Cr in hippocampus region did not change significantly and MI/Cr was increased.. 2.5 mg/d of Aricept can improve general cognition function in patients with aMCI as shown by memory IQ and delayed memory scores. The results of MRS indicate that no apparent change of NAA/Cr and increase of MI/Cr imply improvement of memory with Aricept through activating astrocytes, stabilizing neurons and regulating the signal transmission among synapses.

Topics: Aged; Aged, 80 and over; Amnesia; Aspartic Acid; Cognition; Cognition Disorders; Creatine; Donepezil; Female; Hippocampus; Humans; Indans; Inositol; Magnetic Resonance Spectroscopy; Male; Memory; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines

Topics: Alzheimer Disease; Cerebrovascular Disorders; Cholinesterase Inhibitors; Cognition Disorders; Dementia, Vascular; Diagnosis, Differential; Donepezil; Galantamine; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Terminology as Topic; Treatment Outcome

Topics: Adult; Age Factors; Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Down Syndrome; Female; Humans; Indans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales

Visual hallucinations (VHs) are common psychiatric symptoms in patients with long-standing Parkinson's disease (PD). Treatment with neuroleptics or withdrawal of anti-PD drugs may improve VHs but will worsen motor dysfunctions. The authors report on 3 patients with long-standing PD who were treated with the cholinesterase inhibitor donepezil for the treatment of VHs. Each received a daily dose of 5 mg of donepezil, after reducing or discontinuing anti-PD medications had failed to relieve the VHs. In 2 patients (patient 1, 2), donepezil decreased VHs without worsening motor dysfunctions. In addition, the cognitive status of patient 2 improved. In patient 3, donepezil also resolved VHs, but delusions developed during treatment. After discontinuing donepezil, delusions disappeared and VHs reappeared. Donepezil may ameliorate visual hallucinations in PD patients, but controlled, double-blind trials are necessary to further clarify the effect of this drug on VHs in PD.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Hallucinations; Humans; Indans; Male; Middle Aged; Parkinson Disease; Piperidines; Psychomotor Disorders; Severity of Illness Index

To define the actual knowledge of the impact of drugs for the treatment of dementia on the improvement of cognition in aging and mild cognitive impairment.. We conducted a Medline search for studies with the parameters drug and cognition. Only drugs that had demonstrated cognition improvements in dementia according to actual methodological standards were included. Drugs had to be approved in at least one American or European nation.. Donepezil, galantamine, Ginkgo biloba EGb 761 (definition see editorial), memantine and rivastigmine fulfilled these criteria. There were no systematic investigations on the effects of these drugs on cognition in healthy adults or patients with mild cognitive impairment (MCI). Regarding Ginkgo biloba, two studies on MCI patients could be identified. In healthy adults, we could only include one study investigating donepezil and seven investigating Ginkgo biloba EGb 761. According to the findings, donepezil significantly increased the percentage of REM sleep and REM density, whereas REM latency was reduced. This was interpreted as a sign of improved cognition. Ginkgo biloba EGb 761 improved cognition in healthy controls according to Delayed Free Recall and Delayed Recognition of the WAIS-III and the Color Naming of the Stroop Test as well as in MCI in Digit Copying, Dual Coding Task and speed of response on a computerized version of a classification task. The highest effects were observed after 6 weeks of treatment with 180 mg/d.. Due to the lack of standard procedures for investigating cognition improvement in healthy aging, results have to be interpreted cautiously. In healthy adults as well as in individuals categorized as having MCI, Ginkgo biloba EGb 761 improved cognition in some but not all neuropsychological tests. The single positive result with donepezil raises hope that other drugs may also contribute to cognitive improvement, even in healthy adults. However, the data do not allow any conclusions regarding an improvement following a specific "neuropsychological cluster." Studies on prevention have not been completed so far.

Topics: Adult; Aged; Aged, 80 and over; Aging; Cognition; Cognition Disorders; Dementia; Donepezil; Female; Galantamine; Ginkgo biloba; Humans; Indans; Male; MEDLINE; Middle Aged; Nootropic Agents; Piperidines; Plant Extracts

Topics: Animals; Brain; Cognition Disorders; Dioxoles; Drug Industry; Humans; Piperidines; Receptors, AMPA; Schizophrenia

Donepezil has been shown to improve aspects of cognitive functioning in persons with Alzheimer's disease (AD), but its impact on instrumental activities of daily living has received little attention. In a within-subject design, 24 community-dwelling persons with AD were treated with open-label donepezil over a 12-month period. To assess functional abilities, a brief, objective measure of instrumental activities of daily living skills was used (Texas Functional Living Scale; TFLS). Global cognitive abilities were assessed with the Mini-Mental State Examination (MMSE). Changes in TFLS and MMSE scores were much the same. Improvements on the TFLS and MMSE were seen over a 3-month period. At 12 months, both TFLS and MMSE scores declined slightly below baseline. These results support an effect of donepezil on cognitive measures and day-to-day function and also suggest that the MMSE reflects well the actual functional ability of persons with moderate AD.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Piperidines

Topics: Adult; Brain Injuries; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Male; Neuropsychological Tests; Piperidines

Topics: Adolescent; Adult; Alzheimer Disease; Antimetabolites; Child; Cholinesterase Inhibitors; Cognition Disorders; Cycloserine; Donepezil; Drug Therapy, Combination; Humans; Indans; Neuropsychological Tests; Piperidines

The physiological interrelationships between cognitive impairments, neurotransmitter loss, amyloid processing and energy metabolism changes in AD, cholinergic dementia and Down's syndrome are largely unknown to date. This report contains novel studies into the association between cognitive function and cerebral metabolism after long-term selective CNS cholinergic neuronal and synaptic loss in a rodent model. We measured local cerebral rates of glucose utilization ((14)C-2-deoxyglucose) throughout the brains of awake rats 4.5 months after bilateral intraventricular injections of a cholinotoxic antibody directed against the low-affinity NGF receptor (p75 NGF) associated with cholinergic neurons (192 IgG-saporin). Permanent cholinergic synapse loss was demonstrated by [(3)H]-vesamicol in vitro autoradiography defining presynaptic vesicular acetylcholine (ACh) transport sites. While other metabolic studies have defined acute and transient glucose use changes after relatively nonspecific lesions of anatomical regions containing cholinergic neurons, our results show sustained reductions in glucose utilization in brain regions impacted by cholinergic synapse loss, including frontal cortical and hippocampal regions, relative to glucose use levels in control rats. In the same animals, impaired cognitive spatial performance in a Morris water maze was correlated with reduced glucose use rates in the cortex and hippocampus at this time point, which is consistent with increased postmortem cortical and hippocampal amyloid precursor protein (APP) levels (45, 46). These results are consistent with the view of cholinergic influence over metabolism, APP processing, and cognition in the cortex and hippocampus.

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal; Autoradiography; Behavior, Animal; Cerebral Cortex; Cholinergic Agents; Cognition Disorders; Deoxyglucose; Disease Models, Animal; Female; Glucose; Hippocampus; Immunotoxins; In Vitro Techniques; Injections, Intraventricular; Maze Learning; N-Glycosyl Hydrolases; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor; Ribosome Inactivating Proteins, Type 1; Saporins; Synapses; Wakefulness

Cholinesterase inhibitors are known to enhance cognitive function among patients with dementia of the Alzheimer's type. It is quite possible that this clinical benefit may extend to other patient groups, yet this issue awaits further exploration. This study examines the use of the cholinesterase inhibitor donepezil in the treatment of patients with a history of brain injury and subsequent cognitive impairment. The sample was comprised of 53 ambulatory psychiatric patients who were receiving care for psychiatric sequelae of brain injury. In this sample, residual cognitive impairment was treated with adjunctive donepezil. This study reports the clinical assessments of this patient sample in outpatient follow-up for up to two years duration. Assessments of cognition with the Wechsler Adult Intelligence Scale-Revised and the Hooper Visual Organization Test were obtained on a subset of this sample (N = 22). Clinician assessment ratings were analyzed for the entire sample. Results indicated an improvement in full-scale IQ (t = 2.5, p = 0.02) score as well as clinician-based ratings (t = 12.2, p < 0.0001). Further research will likely delineate whether specific types of brain injuries are most responsive to cholinesterase inhibitors. These findings suggest that donepezil may enhance clinical response by complementing the medication management of other concomitant psychiatric disturbances related to brain injury.

Topics: Adult; Brain Injuries; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Intelligence; Male; Middle Aged; Piperidines; Retrospective Studies; Treatment Outcome

A case of hypnopompic hallucinations associated with donepezil is described. Electroencephalogram (EEG) and sleep EEG changes are common in Alzheimers Disease and acetylcholinesterase inhibitor drugs can affect rapid eye movement sleep and alertness. The importance of assessing sleep in patients treated with these drugs is discussed.

Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Cognition Disorders; Diagnosis, Differential; Donepezil; Electroencephalography; Hallucinations; Humans; Indans; Insecta; Male; Middle Aged; Personality; Piperidines; Sleep, REM

Topics: Aged; Cholinesterase Inhibitors; Cognition Disorders; Dementia, Multi-Infarct; Donepezil; Drug Overdose; Female; Humans; Indans; Piperidines; Poison Control Centers

Topics: Alzheimer Disease; Brain Injuries; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines

Behavioral abnormalities are common in Alzheimer disease (AD); cholinergic treatment reduces the behavioral disturbances of some patients with AD. Characterizing the pretreatment profile of patients who are likely to respond to cholinergic therapy will aid the efficient use of clinical resources.. To determine the baseline behavioral profile for 86 patients with AD treated with the cholinesterase inhibitor donepezil hydrochloride.. Open-label retrospective study of treatment-related behavioral assessments. Based on previous double-blind placebo-controlled experience using the Neuropsychiatric Inventory (NPI), patients were divided into responder (> or =4-point total NPI score decrease, indicating improvement), unchanged (+/-3-point total NPI score change), or nonresponder (> or =4-point total NPI score increase, indicating worsening) groups. The Mini-Mental State Examination assessed cognitive response.. Behavioral improvement was seen in 35 patients (41%), worsening in 24 (28%), and no change in 27 (31%). Comparison of profiles in behavioral responders vs nonresponders revealed significantly worse delusions (P = .04), agitation (P = .04), depression (P = .006), anxiety (P = .02), apathy (P = .003), disinhibition (P = .02), and irritability (P<.001) at baseline in responders. Five behaviors changed significantly from baseline, improving for the responders and worsening for the nonresponders: delusions (P = .003 for nonresponders, P = .004 for responders), agitation (P = .01), anxiety (P = .006 for nonresponders, P = .004 for responders), disinhibition (P = .02 for nonresponders, P = .05 for responders), and irritability (P = .003 for nonresponders, P = .001 for responders). The behavioral changes were dose dependent. Cognition did not change significantly with donepezil treatment within any group.. Donepezil has psychotropic properties, and pretreatment behaviors help predict patients' responses to treatment.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Mental Disorders; Neuropsychological Tests; Piperidines; Prognosis; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Topics: Animals; Clinical Trials as Topic; Cognition Disorders; Humans; Nootropic Agents; Piperidines; Proline; Rats; Rats, Wistar

Recent studies suggest that apolipoprotein E (apoE) plays a specific role in brain cholinergic function and that the E4 allele of apoE (apoE4), a major risk factor for Alzheimer's disease (AD), may predict the extent of cholinergic dysfunction and the efficacy of cholinergic therapy in this disease. Animal model studies relevant to this hypothesis revealed that apoE-deficient (knockout) mice have working memory impairments that are associated with distinct dysfunction of basal forebrain cholinergic neurons. Cholinergic replacement therapy utilizing M1-selective muscarinic agonists has been proposed as effective treatment for AD patients. In the present study, we examined whether the memory deficits and brain cholinergic deficiency of apoE-deficient mice can be ameliorated by the M1-selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline), [AF150(S)]. Treatment of apoE-deficient mice with AF150(S) for 3 weeks completely abolished their working memory impairments. Furthermore, this reversal of cognitive deficit was associated with a parallel increase of histochemically determined brain choline acetyltransferase and acetylcholinesterase levels and with the recovery of these cholinergic markers back to control levels. These findings show that apoE deficiency-related cognitive and cholinergic deficits can be ameliorated by M1-selective muscarinic treatment. They also provide a novel model system for development and evaluation of therapeutic strategies directed specifically at the AD patients whose condition is attributed to the apoE genotype.

Topics: Acetylcholinesterase; Animals; Apolipoproteins E; Brain; Choline O-Acetyltransferase; Cholinergic Fibers; Cognition; Cognition Disorders; Male; Maze Learning; Mice; Mice, Knockout; Muscarinic Agonists; Piperidines; Reaction Time; Swimming; Thiazoles

We have previously demonstrated that a lateral fluid percussion-induced traumatic lesion of the right parietal cortex can lead to a deficit in a conditioned freezing response and that this deficit can be attenuated by both pre- and postlesion administration of the NMDA receptor antagonist dizocilpine. In the present study, we investigated the effects of eliprodil, a noncompetitive NMDA receptor antagonist acting at the polyamine modulatory site, which also acts as a Ca2+ channel blocker, on the trauma-induced conditioned freezing deficit. Eliprodil produced a 50% reduction in this deficit when administered as three 1 mg/kg injections i.v. at 15 min, 6 h, and 24 h following the lesion. Approximately the same degree of protection was afforded when 2 x 1.5 mg/kg were administered 6 and 24 h and equally at 12 and 24 h after surgery (56% and 59%, respectively). A single treatment (3 mg/kg) at 24 h was ineffective against the deficit. The protection afforded with treatment at 6 and 24 h after lesion was dose dependent, with a minimal active dose of 2 x 0.75 mg/kg. These data complement those previously published on the ability of eliprodil to reduce lesion volume following traumatic brain injury and show, in addition, that the neuroprotective effect has functional consequences.

Topics: Analysis of Variance; Animals; Brain Injuries; Cognition Disorders; Conditioning, Classical; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Fear; Male; Neuroprotective Agents; Parietal Lobe; Piperidines; Rats; Rats, Sprague-Dawley; Time and Motion Studies; Time Factors

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Basal Ganglia Diseases; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Piperidines; Risperidone

Treatments in Alzheimer's disease include treatment of cognitive impairment and behavioral manifestations (agitation, depression, anxiety, delusions). It should be noted that many non cognitive behaviors may have some relations to underlying cognitive impairment. In the not too distant future, physicians can expect to see a variety of medications and controversies over the benefits of slowing symptoms with cholinergic therapeutics approved for clinical use and (or) preventing progression of Alzheimer's disease assessed in clinical trials will emerge.

Topics: Aggression; Alzheimer Disease; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Carbamates; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Depression; Donepezil; Humans; Indans; Mental Disorders; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Sleep Wake Disorders; Tacrine

Delirium is a common complication of dementia and may produce considerable morbidity. In addition to psychotic symptoms such as hallucinations and delusions, delirium may produce considerable agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. The main approach to delirium is to treat any underlying medical problem that could cause the delirium. However, delirium is not always reversible, and there is no specific treatment for persistent delirium. The authors present a case of delirium complicating a preexisting dementia that resolved rapidly following initiation of the cholinesterase inhibitor donepezil, suggesting that cholinergic dysfunction may have played a role in the etiology of this patient's delirium. Future research needs to be directed at the issue of cholinergic activity in delirium through monitoring of serum anticholinergic activity and its response to procholinergic therapy.

Topics: Aged; Alcohol Withdrawal Delirium; Cholinesterase Inhibitors; Cognition Disorders; Delirium; Dementia; Donepezil; Humans; Indans; Male; Mood Disorders; Piperidines; Treatment Outcome

Both human essential hypertension and genetically induced hypertension in rats have been associated with a range of impairments of cognitive ability. The spontaneous hypertensive rat (SHR) previously has been shown to exhibit a decrease in the expression of brain nicotinic acetylcholine receptors, a factor that could play a role in the impaired ability of this strain in the performance of learning and memory-related tasks. The purpose of this study was to help determine whether task impairment by SHR was related to the reduced expression of central nicotinic acetylcholine receptors. Twelve-week-old SHR were tested in two phases of a water maze (spatial memory) task, and their performance was compared with that of two age-matched normotensive strains, Wistar Kyoto (WKY) and Wistar rats. During Phase 1, SHR exhibited significantly increased latencies to locate a hidden platform as compared with either WKY or Wistar rats. During Phase 2 (subsequent series of trials after a 4-day inter-phase period), where rats were required to find a new platform location, SHR again exhibited significantly impaired performance compared to the normotensive strains. In a single trial passive avoidance paradigm, SHR again displayed significantly reduced avoidance behavior as compared with both WKY and Wistar rats. In consecutive coronal sections, the density of [3H]cytisine binding sites was decreased in SHR by up to 25% in about half of the brain regions examined, with the deficits particularly apparent in cephalic regions. The binding of [125I]alpha-bungarotoxin to brain sections also was decreased in SHR; however, only certain brain areas exhibited significant interstrain differences. These alterations in the expression of putative nicotinic receptor subtypes in SHR were not due to changes in the density of cholinergic neurons since there were no interstrain differences in the binding densities for [3H]vesamicol, which labels the vesicular acetylcholine transporter. Moreover, the magnitude of nicotine-stimulated rubidium efflux from cortical and striatal synaptosomes in vitro was significantly reduced in samples derived from SHR as compared with those from normotensive rats. These results are consistent with the possibility that a reduction in the expression of cortical nicotinic receptors in SHR plays a role in this strain's impaired performance of both spatial and non-spatial learning and memory-related tasks.

Topics: Alkaloids; Animals; Autoradiography; Avoidance Learning; Azocines; Blood Pressure; Brain; Bungarotoxins; Carrier Proteins; Cognition Disorders; Corpus Striatum; Frontal Lobe; Humans; Hypertension; Iodine Radioisotopes; Male; Maze Learning; Membrane Transport Proteins; Organ Specificity; Piperidines; Quinolizines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Nicotinic; Rubidium; Tritium; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins

Topics: Cholinesterase Inhibitors; Cognition Disorders; Dementia; Donepezil; Health Policy; Humans; Indans; Piperidines

Topics: Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Piperidines; Treatment Outcome

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) is a selective and potent sigma receptor ligand. We investigated the effects of NE-100 on phencyclidine (PCP)-induced cognitive dysfunction in rats in a water maze task. NE-100 significantly shortened the PCP-induced prolonged swimming latency as did 1-(cyclopropylmethyl)-4-[2'(4"-fluorophenyl)-2'-oxoethyl]- piperidine monohydrobromide (Dup 734), 4-[2'-(4"-cyanophenyl)-2'-oxoethyl]-1-(cyclopropyl-methyl)pi peridine (XJ 448), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole, all of which are sigma receptor ligands and possibly antagonists. Ritanserin, a 5-HT2 receptor antagonist, also showed a tendency to shorten swimming latencies. Latencies of haloperidol-, cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4-met hyl- aminobenzamide (YM-09151-2)- and sulpiride-, dopamine D2 receptor antagonists, treated groups did not differ from that seen in the PCP-treated group. Thus, PCP-induced cognitive dysfunction may be improved by sigma receptor ligands.

Topics: Animals; Anisoles; Anti-Anxiety Agents; Cognition Disorders; Drug Interactions; Ligands; Male; Phencyclidine; Physical Exertion; Piperidines; Propylamines; Pyrimidines; Rats; Rats, Wistar; Receptors, sigma; Ritanserin; Swimming

Topics: Adult; Cognition Disorders; Confusion; Dibenzocycloheptenes; Drug Therapy, Combination; Female; Humans; Middle Aged; Piperidines

Topics: Aged; Butyrophenones; Cognition Disorders; Female; Humans; Male; Piperidines; Tranquilizing Agents

Topics: Antidepressive Agents; Cognition Disorders; Dementia; Depression; Humans; Hysteria; Indoles; Male; Paranoid Disorders; Piperidines; Schizophrenia; Schizophrenic Psychology